Rol Del Sistema Inmune en La Hipertension

Physiol Rev 97: 1127–1164, 2017
Published May 31, 2017; doi:10.1152/physrev.00031.2016
ROL DEL SISTEMA INMUNE EN LA

HIPERTENSIÓN
Bernardo Rodríguez-Iturbe, Héctor Pons y Richard J. Johnson
Servicio Renal, Hospital Universitario, Universidad del Zulia, e Instituto Venezolano de Investigaciones Científicas (IVIC)-Zulia,
Maracaibo, Venezuela; y División de Enfermedades Renales e Hipertensión, Universidad de Colorado, Anschutz Campus, Aurora,
Colorado.
Rodríguez Iturbe B, Pons H, Johnson RJ. Rol del Sistema Inmune en la Hipertensión. Physiol
L Rev 97: 1127–1164, 2017. Publicado el 31 de mayo, 2017; doi:10.1152/physrev.00031.2016. —

La hipertensión arterial está presente en más de mil millones de adultos en todo el mundo y es el
factor de riesgo modificable más importante de muerte por enfermedad cardiovascular. Aunque son
muchos los factores que contribuyen a la patogénesis de la hipertensión, un gran número de inves-
tigaciones realizadas en numerosos laboratorios de todo el mundo establecieron firmemente el papel del sistema
inmune. Los fármacos inmunosupresores y la inhibición de citoquinas individuales previenen o mejoran la
hipertensión experimental, y estudios en cepas de ratón genéticamente modificadas han demostrado que los
linfocitos son partícipes necesarios en el desarrollo de la hipertensión y en la lesión hipertensiva de órganos.
Además, la reactividad inmunitaria puede ser el motor de la hipertensión en las enfermedades autoinmunitarias.
La infiltración de células inmunitarias, el estrés oxidativo y la estimulación del sistema de angiotensina
intrarrenal son inducidos por la activación de la inmunidad innata y adaptativa. La hipertensión arterial es el
resultado de los efectos combinados de la alteración de la relación entre la presión y la natriuresis inducida por la
inflamación, la relajación vascular disfuncional y la hiperactividad del sistema nervioso simpático. Los
desequilibrios entre las respuestas efectoras proinflamatorias y las respuestas antiinflamatorias de las células T
reguladoras determinan en gran medida la gravedad de la inflamación. Estudios experimentales y humanos han
descubierto autoantígenos (proteínas isoketal-modificadas y proteína 70 de choque térmico) de potencial
relevancia clínica. Nuevas investigaciones sobre la reactividad inmunitaria en la hipertensión podrían dar lugar a
la identificación de nuevas estrategias para el tratamiento de la enfermedad.
I. INTRODUCTION 1127 proved therapeutic options, is uncontrolled in 8 –12% of

II. IMMUNITY IN EXPERIMENTAL ... 1128 the patients (36).
III. OVERVIEW OF THE IMMUNE RESPONSE 1132
IV. IMMUNE CELLS AND HYPERTENSION 1133 The interaction of environmental, genetic, anatomical,
V. CYTOKINES IN EXPERIMENTAL ... 1136 neural, endocrine, humoral, and hemodynamic factors
VI. INNATE IMMUNITY IN HYPERTENSION 1139 plays a role in essential hypertension. These factors have
VII. ADAPTIVE IMMUNITY IN ... 1142 been condensed in the Page Mosaic theory (202), about
VIII. AUTOIMMUNITY IN ... 1144 which it has been said that “its weakness is that it cannot
IX. PATHOPHYSIOLOGY OF ... 1145
be proved wrong” (73). Immunity and autoimmunity do
X. IMMUNE REACTIVITY IN PATIENTS ... 1149
not appear in the octagonal Page Mosaic; nevertheless,
XI. GUT MICROBIOTA AND HYPERTENSION 1152
XII. CONCLUDING REMARKS 1153 Harrison (92) has noted that inflammation is present
upstream or downstream of each one of the intercon-
nected factors.
I. INTRODUCTION
The initial studies that examined the role of immune cells in
Hypertension is defined as blood pressure equal to or hypertension were done nearly half a century ago (196,
greater than 140/90 mmHg and occurs in 25– 43% of the
305), but research on immunity in the pathogenesis of hy-
world population older than 18 yr, representing the lead-
pertension was rare until 16 –18 yr ago when a reawakened
ing modifiable risk factor for death resulting from car-
diovascular disease (321). High blood pressure may be interest fueled an exponential increase in the number of
secondary to a number of causes, but in the vast majority publications in this topic (228). This paper reviews the re-
of the patients, it does not have a recognized etiology. search that has established the pivotal contribution of the
These patients are collectively grouped in what is known immune system in the pathogenesis of essential hyperten-
as primary or essential hypertension that, despite im- sion.
0031-9333/17 Copyright © 2017 the American Physiological Society 1127

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RODRIGUEZ-ITURBE ET AL.
II. IMMUNITY IN EXPERIMENTAL MODELS mation in the kidneys of adult SHR suggested the participation
OF HYPERTENSION of immunity, and early studies documented reduced delayed-
type hypersensitivity suggesting impaired cell mediated immu-
nity. This led to a series of investigations aimed to modify
A. Genetic Models of Hypertension
cell-mediated immunity with thymocytotoxic antibodies, thy-
Experimental interventions directed to suppress immune mosin (extract of calf thymus), thymus grafting, and adminis-
reactivity in genetic models of hypertension are shown in tration of interleukin (IL)-2. These investigations had conflict-
TABLE 1 that includes the magnitude of the antihypertensive ing results with some studies ameliorating, others aggravating,
effects of each treatment. and yet others having no effect on hypertension (6, 266, 267).
These mixed results were likely due to the lack of discrimina-
1. Spontaneously hypertensive rat (SHR) tion between proinflammatory and immune suppressor T cells
in the early experimental studies.
In 1963, Okamoto and Aoki (194) described a strain of rats
that are normotensive 3– 4 wk after birth and develop progres- Subsequent experiments evaluated the effects of immuno-
sive hypertension as they age. The finding of arteriolar inflam- suppression on blood pressure. Administration of cyclo-
Table 1. Hypertensive animal strains in which suppression of immunity/inflammation ameliorated or prevented hypertension
Blood Pressure, mmHg
Strain Experimental Strategy/Treatment Untreated Treated
Spontaneously hypertensive rat (SHR) Cyclophosphamide (132) 172 153

Mycophenolate mofetil (222) 198 147
Inhibition of NF␬B activation (218) 198 127
Suppression of oxidative stress (189) 195 149
(223) 207 179
(316) 175 149
Stroke-prone SHR Increase CD4⫹CD25⫹Foxp3 cells (Treg cells) by sympathetic 175 150
denervation (128)
Dahl’s salt sensitive rat Inhibition of pyrimidine synthesis (283) 250 200
Mycophenolate mofetil (174) 139* 122*
Tacrolimus (52) 170* 150*
Tempol (52) 140* 126*
Etanercept (104) 165* 145*
Anti-TGF-␤ antibody (44) 190* 177*
(187) 200* 179*
Anti-IL-6 antibody (94) 149* 138*
Genetic deletion of p67phox (69) 180* 140*
Mesenchymal stem cell transplantation (103) 185* 150*
Mutation of RAG 1 gene (175) 180* 150*
Deletion of the CD247 gene (225) 151* 134*
Mutation in the SH2B3 gene (226) 175* 135*
Lyon rat Neonatal thymectomy (8) 122 111
Cyclophosphamide (9) 175 135
Fawn Hooded rat Inhibition of NF␬B activation (137) 159 128
dTGF rat Inhibition of NF␬B activation (185) 185 162
Cyclosporine A (180) 210 178
Inhibition of p38 MAPK (204) 203 165
NZB mice Cyclosporine A (263) 155* 147*
NZBW mice Anti-IL-4 antibody (285) 87* 68*
Rosiglitazone (291) 139* 127*
Etanercept (290) 150* 130*
Anti-CD20 antibody (170) 141* 127*
Data are systolic blood pressure or mean arterial pressure (*). There is considerable variation in the antihypertensive effect of the various
treatments. Reference numbers are given in parentheses. See text for definitions.
1128 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

IMMUNITY IN HYPERTENSION
phosphamide (132), mofetil mycophenolate (MMF) (222), tion with reduced tissue inflammation, and the authors con-
or suppressing the overactivity of the proinflamatory tran- cluded that a “hyperimmune state” was responsible for the
scription factor NF␬B with pyrrolidine dithiocarbamate susceptibility of Dahl SS rats to hypertension (283).
(PDTC) (218) reduced the renal infiltration of immune cells Mattson and co-workers (51, 174) later administered MMF
in tubulointerstitial areas, suppressed the oxidative stress, or Tacrolimus and obtained 50 – 60% reduction in the renal
and corrected the hypertension. Amelioration of hyperten- tubulointerstitial immune cell infiltration with amelioration
sion in the SHR was also found in association with reduc- of hypertension and proteinuria. Subsequent studies dem-
tion of renal inflammation resulting from treatments di- onstrated that a high-salt diet induced intrarenal activation
rected to correct oxidative stress. These treatments included of NF␬B and that T cells infiltrating the kidney had in-
administration of melatonin (189) and antioxidant-rich di- creased mRNA expression of proinflammatory cytokines
ets (223) or improving nitric oxide (NO) availability with (271). SS hypertension was associated with overexpression
sildenafil (316), which inhibits the degradation of cGMP of the p67phox, gp91phox, and p47phx subunits of
(mediator of NO biological actions). NADPH oxidase (52), and genetic deletion of p67phox
ameliorated hypertension (69). The interaction between in-
In summary, these studies are all suggestive that renal inflammation and oxidative stress was highlighted by the re-
flammation plays a role in the pathogenesis of hypertension duction in NF␬B activation, immune cell infiltration, pro-
of the SHR. teinuria, and hypertension resulting from antioxidant treat-
ments with vitamin C and vitamin E (272, 273). Reduction
2. Stroke-prone spontaneously hypertensive in renal tubulointerstitial inflammation with MMF also
rat (SPSHR) prevents the hypertension resulting from a high-protein
(53) and a high-fat diet (250) in Dahl SS rats. Anti-
The stroke-prone strain was established as a substrain of the inflammatory agents without immune suppressive activity
SHR rats with severe hypertension and high stroke suscep- do not modify SS hypertension (98, 308).
tibility (195). The SPSHR has increased sympathetic ner-
vous system (SNS) activity (317) and a relative reduction of The role played by tubulointerstitial inflammation was also
anti-inflammatory CD4⫹CD25⫹Foxp3 regulatory T demonstrated in studies where mesenchymal stem (immu-
(Treg) cells in the spleen. Splenic denervation increased the nosuppressive) cells were transplanted into the renal me-
proportion of Treg cells and delayed the development of dulla of uninephrectomized Dahl’s SS rats and obtained
hypertension in the SPSHR (128). Inflammation in the cen- improvement of the inflammatory infiltrate and correction
tral nervous system is less likely responsible for the hyper- of hypertension (103).
tension since reduction in microglial activation with mino-
cycline does not modify the blood pressure (268). Recent research has used Dahl SS rats to identify the role of
genes associated with hypertension in genome-wide associ-
3. Dahl salt-sensitive rat ation studies (GWAS). In particular, the CD247 gene and
the SH2B3 (LNK) gene have been carefully evaluated. The
In 1962, Dahl et al. (43) utilized selective outbreeding of CD247 gene is part of the T cell receptor complex, and its
Sprague-Dawley rats to generate two lines of rats that dif- deletion in the Dahl rat (225) gave evidence of the impor-
fered by their blood pressure response to a high-salt diet: a tance of antigen recognition in SS hypertension (discussed
salt-sensitive (SS) line that developed hypertension and salt- in sect. VII). SH2B3 plays a suppressive role in the activa-
resistant (SR) line that remained normotensive. tion of immune responses and cytokine signaling (54). Saleh
et al. (230) demonstrated that deficiency in SH2B3 gene
Early studies by Dahl’s group noted that intrarenal inflam- resulted in increased inflammation in the kidneys and aorta
mation was present in SS rats and became more prominent and exaggerated response to angiotensin II infusions. Bone
on a high-salt diet (117). While glomerular injury and scle- marrow transplantation experiments showed that loss of
rosis developed in these rats (254), hypertension was SH2B3 gene in endothelial cells was responsible for these
strongly correlated with tubulointerstitial inflammation findings. Rudemiller et al. (226) induced a mutation in the
(173, 297). CD4⫹ (helper) and CD8⫹ (cytotoxic) T lym- SH2B3 that was predicted to affect a phosphotyrosine-
phocytes infiltrate in equal numbers and are primarily lo- binding site in the SH2 domain and thereby suppress signal
cated in areas surrounding damaged glomeruli and blood transduction. The mutation, in fact, ameliorated hyperten-
vessels (51). sion and inflammation. These findings could be explained in
part by a selective increase in Tregs in the mutant rats asso-
Early investigators administered the compound HR325 ciated with a high-salt diet. A higher ratio of Tregs to pro-
(cyanocyclopropyl trifluoromethyl acrylamide), an immu- inflammatory T cells could be a factor in the attenuation of
nosuppressive drug that inhibits pyrimidine synthesis and inflammation. Bone marrow cross-transplantation demon-
suppresses both humoral and cellular immunity, to Dahl SS strated that the findings were dependent on SH2B3 mutant
rats. Salt-induced hypertension was improved in associa- bone marrow cells. Contraction and dilatation of resistance
Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1129

vessels were unmodified in the mutant rats; therefore, the with only minimal improvement in histological renal dam-
improvement in hypertension could not be explained by age (181). Nevertheless, other studies from the same group
changes in vascular function. found that suppression of inflammation by inhibition of
NF␬B as well as by treatment with cyclosporin A, could
4. Lyon rat ameliorate both angiotensin II-induced inflammatory dam-
age and hypertension (180, 185). Park et al. (204) blocked
The Lyon hypertensive (LH) and normotensive (LN) rats the proinflammatory mitogen-activated protein kinase
resulted from selective breeding from the same Sprague- (MAPK) pathway and found amelioration of hypertension
Dawley colony. The LH rats present with both spontaneous in association with reduction in the inflammatory cell infil-
and SS hypertension, low circulating renin, increased body tration in the kidneys and heart.
weight, hyperlipidemia, proteinuria, and increased insulin-
to-glucose ratio (70, 232). The participation of the immune Taken together, these studies suggest that high levels of
system in the hypertension of LH rats was suggested by the angiotensin and associated proinflammatory cytokines may
finding that neonatal thymectomy and treatment with cy- induce renal injury independently of hypertension. Never-
clophosphamide improved hypertension (8, 9). theless, once injury is established, inflammation-induced
damage contributes to the development and severity of hy-
pertension
5. Fawn hooded (FH) rat
7. Sabra rat
The FH rat strain was introduced as an outbred stock of rats
with a hemorrhagic tendency due to a platelet defect (281).
The Sabra rats have SS and SR phenotypes genetically dif-
Selective mating among FH siblings resulted in the breeding
ferent from Dahl strains (16). In the Sabra rat, oxidative
of a hypertensive (FHH) strain and a normotensive strain.
stress and inflammation both precede and accompany hy-
The FHH rats showed a correlation between the severity of
pertension (237).
hypertension and the glomerular and tubulointerstitial in-
jury as well as with plasma renin levels (144).
8. New Zealand Black (NZB) mouse
The participation of renal inflammation in the pathogenesis
Initial studies on the blood pressure of the NZB mouse
of hypertension in the FHH rats was suggested by the dem-
strain gave contrasting results. Svendsen (263), using intra-
onstration that activation of NF␬B early in life was a critical
carotid determination of blood pressure, found the NZB
factor in the development of hypertension; indeed, perinatal
mice to be hypertensive and reported that high blood pres-
PDTC treatment ameliorated hypertension in association
sure was improved with cyclophosphamide treatment and
with reduction in renal immune cell infiltration, albumin-
that athymic NZB mice did not develop hypertension. In con-
uria, and glomerulosclerosis (137).
trast, Rudofsky et al. (227), using tail-cuff methodology, re-
ported the NZB mice to be normotensive despite the presence
6. dTGF rat of renal disease. Nevertheless, the offspring (NZBWF1) of the
cross of NZB mice with the New Zealand White mice were
Double transgenic rats (dTGF) for human angiotensinogen hypertensive in association with nephritis (227) and had many
and renin were developed by crossing a transgenic strain for features resembling systemic lupus erythematosus (SLE) in hu-
human angiotensinogen and a transgenic strain for human mans (102, 169, 170, 179).
renin (19). Involvement of the immune system in the dTGR
is an early event, as noted by complement activation in the
blood vessel walls with inflammatory cell infiltration that B. Experimentally Induced Hypertensive
occurs before albuminuria develops (240). The dTGF rats Models
have been used for studying the effects of severe angiotensin
II-mediated hypertension and tissue damage. In this model 1. Renal infarct model
of hypertension, the administration of dexamethasone,
MMF, or etanercept [a recombinant fusion protein of the The first studies that associated immunity and hypertension
extracellular ligand-binding domain of tumor necrosis fac- were done in rats with partial renal infarct and contralateral
tor (TNF) receptor type 2], could reduce the immune cell nephrectomy that developed anti-kidney and anti-artery
infiltration in the kidneys, resulting in less fibrosis and al- antibodies. Furthermore, “suppressants of antibody reac-
buminuria but without effect on hypertension, thus sepa- tions” (cortisone and 6-mercaptopurine), as well as thymec-
rating the tissue injury and the blood pressure effects of tomy, ameliorated hypertension (305). Hypertension could
angiotensin II (186). The independence of hypertension and be transferred by spleen cells of hypertensive rats to normo-
the tissue injury in this model were further shown in studies tensive recipients (196). The same model was used by
that normalized blood pressure with triple antihypertensive Svendsen for a series of investigations (260, 261) in mice
treatment (hydralazine, reserpine, and hidrochorothiazide) with normal thymus (haired mice) and athymic (nude) mice.

He described an early hypertension (30 – 40 days postoper- 4. Cellophane-wrapped kidneys

atively) that was similar in the haired and nude mice. The
early hypertension was followed by a late, chronic hyper- In 1939, Irving Page reported that cellophane wrapping of the
tension in the haired mice that was absent in athymic mice. kidneys caused hypertension (201). He postulated that the
The administration of cyclophosphamide did not modify cellophane-induced fibrocollagenous perinephritic reaction
the early hypertension but ameliorated the late hyperten- compressed the kidney and caused intrarenal ischemia, thus
sion and corrected the renal “round cell” infiltration that resembling the hypertension obtained by Goldblatt with con-
accompanied hypertension in the haired mice. Thymus striction of the renal arteries. Concordant with this view, hy-
grafts restored the late hypertension and the renal immune pertension in the Page kidney was traditionally attributed to
cell infiltration in the nude mice. He concluded that in this increased levels of systemic angiotensin II (95). However, in-
model there existed an early thymus-independent hyperten- vestigations by Vanegas et al. (286) showed that cellophane-
sion and a chronic thymus-dependent hypertension. This wrapped kidneys developed intense tubulointerstitial inflam-
was one of the earliest and best documented studies of role mation and increased intrarenal angiotensin II concentra-
of T cells in experimental hypertension. tion while plasma angiotensin II levels were unmodified.
Administration of MMF suppressed the immune cell infil-
2. Deoxycorticosterone acetate tration, reduced the intrarenal angiotensin II, and prevented
(DOCA)-salt hypertension hypertension. These results strongly suggest a role of im-
mune cell activation in this model.
In 1970, Gardner et al. (79) studied a model of severe hy-
pertension induced by a combination of subcutaneous im- 5. Chronic low-dose lead exposure
plantation of DOCA pellets, high-salt diet, and unilateral
nephrectomy. They showed that cyclophosphamide pre- Chronic lead exposure results in adrenergic overactivity
vented vascular lesions, although in association with a high (279) and increased oxidative stress (288) and has been
mortality. This work did not report if immunosuppressive associated with hypertension in humans (21, 33). The role
treatment improved hypertension. Subsequently, Olsen of tubulointerstitial inflammation in the pathogenesis of
(197) found that hypertension could be transferred to nor- lead-induced hypertension was evaluated in rats that re-
motensive rats by spleen cells of rats that had been hyper- ceived 14 wk of a low dose of lead acetate (100 ppm in the
tensive for 3 mo or more and suggested that hypertension drinking water). These rats developed progressive hyper-
resulted from delayed hypersensitivity directed against ar- tension, oxidative stress, interstitial accumulation of lym-
terial walls. In this model, Svendsen (262) showed that, as phocytes and macrophages, activation of NF␬B, and in-
in the experiments with the renal infarct model, the initial creased intrarenal angiotensin II. The administration of
hypertension was independent of the thymus, whereas athy- MMF corrected the renal inflammation and the oxidative
mic mice did not develop the late salt-driven hypertension. stress, normalized the renal angiotensin II, and prevented
Grafting of thymus in the athymic mice restored the capac- the development of hypertension (24).
ity to develop the late hypertension and intrarenal inflam-
mation. 6. Angiotensin II infusion
3. Prenatally programmed hypertension Angiotensin II infusions have been given to mice or rats in
doses ranging from 0.694 (41) to 3,600 ng·kg⫺1·min⫺1
Reduction in the nephron number resulting from maternal (147) to evaluate the various aspects of the pathogenesis of
protein and caloric malnutrition during pregnancy is a risk angiotensin II-induced hypertension, endothelial dysfunc-
factor for adult hypertension (159). Stewart et al. (255) tion, and tissue injury. Administration of angiotensin II is
examined the role of renal inflammation and oxidative usually made by subcutaneously placed osmotic minipumps
stress in prenatally programmed hypertension. They gave a and the duration of the infusion is 2– 4 wk. Wilcox’s group
low-protein diet to pregnant Sprague-Dawley rats during (129) studied the slow pressor response of low doses of
the last 9 days of gestation and the resulting offspring be- angiotensin. They have shown that a subcutaneous infusion
came hypertensive between 6 and 8 wk of life. At 4 wk of of angiotensin II at a rate of 400 ng·kg⫺1·min⫺1 in mice
age, before they became hypertensive, the rats developed does not elevate the blood pressure by day 6, but induces
renal infiltration of immune cells and oxidative stress. The hypertension after 10 days. This slow pressor response is
administration of MMF or tempol (SOD mimetic) at days caused, at least in part, by oxidative stress, because it is
21– 42 of age suppressed the lymphocyte and macrophage corrected with tempol. Infusion rates of 800 –1,000
infiltration of the kidney and the oxidative stress and pre- ng·kg⫺1·min⫺1 cause an abrupt increase in blood pressure
vented hypertension. The blood pressure remained normal that is sustained with a tendency to plateau after 2 wk.
after discontinuation of the drugs. This study showed that Effects related to the immune activation induced by angio-
renal inflammation is a critical element in the pathogenesis tensin II infusions are investigated in 2– 4 wk studies. An-
of prenatally programmed hypertension. giotensin II doses in the range of 800 –1,000 ng·kg⫺1·min⫺1

are generally used in investigations directed to evaluate re- by Baylis et al. (15) and Ribeiro et al. (215). The sympa-
nal, vascular, or heart injury because these doses cause more thetic nervous system (231), the renal renin-angiotensin sys-
reproducible histological damage. However, it should be tem (127), and endothelin (292) participate in the develop-
kept in mind that after 2 wk high infusion rates of angio- ment of L-NAME-induced hypertension. Histologically,
tensin II cause hypokalemia, likely resulting from angioten- suppression of NOS is associated with tubulointerstitial im-
sin II-stimulated aldosterone production (129), and renal mune cell infiltration and fibrosis, glomerulosclerosis, and
tubulointerstitial damage associated with potassium deple- arteriolar lesions. Administration of L-NAME for 3 wk to
tion may be a confounding feature (257). normotensive rats results in a progressive elevation of the
blood pressure that returns to normal levels a week after
Doses in the intermediate range (490 – 600 ng·kg⫺1·min⫺1) discontinuation of L-NAME. Subsequent administration of
are administered in investigations that focus on the nature a high-salt diet results in hypertension. The role of renal
and characteristics of the immune cell infiltration (90, 135). inflammation resulting from L-NAME treatment in the sub-
Surprisingly, very few data exist in relation to the levels of sequent development of SS hypertension was investigated
circulating angiotensin II levels induced by angiotensin in- by administering MMF in association with L-NAME. MMF
fusions. Doses of 200 ng·kg⫺1·min⫺1 in mice are reported did not modify the hypertension that occurred during the
to result in angiotensin II plasma concentrations of 51 ⫾ 8 administration of L-NAME-induced hypertension but sup-
fmol/ml, which correspond to levels observed in the physi- pressed the renal injury and immune cell infiltration and the
ological increase resulting from a low-salt diet. Doses 4 subsequent salt-induced hypertension (213). In the L-
times higher (800 ng·kg⫺1·min⫺1) result in a 10-fold incre- NAME-induced model of hypertension, effector memory
ment in plasma angiotensin II concentration, but pharma- cells accumulate in the kidney, and CD70-deficient mice
cokinetics were not analyzed (162). Therefore, it appears that cannot develop memory T cells are protected from
likely that the doses used in the majority of the studies done post-L-NAME salt-driven hypertension (114).
with angiotensin II infusions result in plasma levels of an-
giotensin II substantially higher than those present in phys- 9. SS hypertension induced by overload proteinuria
iological responses or in physiopathological conditions.
Systemic administration of protein results in proteinuria
It is interesting that in a newly developed mouse model in that is associated with structural glomerular changes (47)
which the murine immune system is replaced by a human and intense tubulointerstitial inflammation (63) and with
immune system, activation and tissue infiltration of im- the development of hypertension in response to a high-salt
mune cells after angiotensin II infusions occurs indepen- diet (1). Treatment with MMF during BSA overload did not
dently of angiotensin II. Correction of hypertension with modify the proteinuria but suppressed the tubulointerstitial
hydralazine and hydrochlorothiazide prevents accumula- infiltration of lymphocytes and macrophages and prevented
tion of T cells in the kidney. Therefore, human T cells infil- the salt-driven hypertension (1).
trate tissues in response to high blood pressure in this model
(113). In summary, immunosuppressive interventions associated
with reduction of inflammation, improvement of oxidative
7. SS hypertension induced by transient angiotensin
stress, and reduction in renal angiotensin II activity have
II infusions
been shown to prevent, improve, or correct hypertension in
Lombardi et al. (156) showed that 2 wk of angiotensin II genetic and experimentally induced models of hyperten-
administration in rats resulted in tubulointerstitial inflam- sion. T and B lymphocytes, monocytes/macrophages, natu-
mation and subtle renal injury associated with loss of peri- ral killer cells, and dendritic cells are the central cellular
tubular capillaries. Subsequent administration of a high- elements in immune-driven reactivity. Their participation
salt diet resulted in hypertension. Suppressing the inflam- in the pathogenesis of hypertension results from the activa-
matory response induced by angiotensin II with the tion of the innate and adaptive pathways of immune reac-
administration of MMF (220) during the time when angio- tivity.
tensin was infused did not modify the hypertension induced
by the hemodynamic effects of angiotensin II but resulted in III. OVERVIEW OF THE IMMUNE
a substantial reduction of the immune cell infiltration, oxi- RESPONSE
dative stress, and tubulointerstitial injury and prevented the
development of post-angiotensin salt-induced hyperten-
Innate immunity is a system of immediate response against
sion.
danger signals. These signals correspond to molecular pat-
8. SS hypertension induced by transient L-NAME terns in pathogenic microorganisms (pathogen-associated
administration molecular patterns or PAMPs) or endogenously generated
cellular stress signals (danger-associated molecular patterns
Inhibition of nitric oxide synthase (NOS) with L-NAME is or DAMPs). These signals are recognized by pattern recog-
an experimental model of hypertension described in 1992 nition receptors (PRR) that engage intracellular pathways

that induce the assembly of caspase-1-activating complexes ated protective response to subsequent antigen exposure.
called inflammasomes. The inflammasomes induce the pro- Cytokines produced by activated CD4⫹ T cells generate
cessing and secretion of a common set of proinflammatory and maintain B-cell humoral immune responses.
cytokines that aim to suppress the harmful element and
induce a form of cell death called pyroptosis (235). There The naive CD4⫹ T cell, depending on the cytokine environ-
are four inflammasomes defined by their NLR protein ment, polarizes to Th1, Th2, Th17, or Treg phenotypes.
(NLRP1, NLRC4, NLRP3, and AIM2) of which the The Th1 phenotype is generated in environment of IL-12
NLRP3 is the one studied in relation to the activation of the and interferon (IFN)-␥ and predominantly secretes IL-2,
innate immunity in hypertension. Among the PRR, the Toll- TNF-␣, and IFN-␥. The Th2 phenotype is generated in IL-4
like receptors (TLRs) are, up to the present time, the only environment and predominantly secretes IL-4 and IL-10.
group that has been shown to be involved in the inflamma- The Th17 phenotype requires IL-6, IL-21, IL-23, trans-
tion associated with hypertension. TLRs are expressed by T forming growth factor (TGF)-␤, and IL-1␤; is activated by
and B lymphocytes, monocytes, dendritic cells, and other aldosterone; and secretes IL-17A, IL-17F, IL-21, and
somatic cells, such as endothelial and vascular smooth mus- IL-22 (77). The Treg phenotype is generated in TGF-␤1
cle cells. The TLRs engage the inflammasome pathway that environment with low concentration of IL-6, and its anti-
is activated by two signals. Signal I includes upregulation of inflammatory activity is exerted by secretion of immuno-
NF-␬B, AP-1, and interferon-regulatory factors which re- suppressive immune factors such as IL-9, IL-10, TGF-␤,
sult in the upregulation of genes that control inflammasome and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and by
components, such as the sensor molecule NLRP3, pro- direct cell-to-cell contact (324).
caspase, pro-IL-1␤, and pro-IL-18. The priming of NLRP3
is a requisite for inflammasome activation except when In the following sections we will discuss the roles of immune
there is constitutive NLRP3 expression, as in macrophages cells, cytokines, and innate and adaptive immunity in ex-
(10, 11). Signal II in the canonical inflammasome activation perimental hypertension.
consists of the detection of PAMPs and DAMPs by NRLP3,
which in turn engages a caspase recruitment domain (ASC) IV. IMMUNE CELLS AND HYPERTENSION
and procaspase which heterodimerize to form active
caspase. The role of caspase in the inflammasome is to cat-
A. T Lymphocytes
alyze the intracellular processing of pro-IL-1␤ and pro-
IL-18 to their biologically active forms (IL-1␤ and IL-18).
The definite demonstration of a specific role for T cells in
The active forms are released to the extracellular space and
the pathogenesis of experimental angiotensin II-induced hy-
drive the inflammation. In addition to offering an immedi- pertension was obtained by Guzik et al. (90) using the
ate defense response, the inflammasome supports an effec- rag1⫺/⫺ mouse that lacks T and B lymphocytes. Angioten-
tive antigen presentation to naive T cells and thereby facil- sin II-induced hypertension is associated with T-cell infil-
itates a subsequent acquired (adaptive) immune response tration in perivascular tissue; oxidative stress; expression of
directed specifically to the corresponding antigen (166). intercellular adhesion molecule 1 (ICAM-1), RANTES, and
The delivery of signal II for inflammasome activation may TNF-␣; and impairment in endothelial-dependent vasodila-
come from cellular efflux of potassium ions, production of tation. All these features were suppressed in the rag1⫺/⫺
mitochondrial ROS, or release of mitochondrial DNA and mouse in association with a blunted blood pressure re-
lysosomal destabilization (323). sponse to angiotensin II or to DOCA-salt. Adoptive transfer
of T cells, but not B cells, restored the response to angioten-
The adaptive immune system is characterized by specific sin II, including hypertension, in the rag1⫺/⫺ mouse.
immune response directed to exogenous or endogenous an-
tigens. The most important effector cells of the adaptive The role of T lymphocytes in Dahl SS rats was subsequently
immune system are T and B lymphocytes. Activation of T demonstrated by Mattson et al. (175) who used zinc finger-
cells requires that antigens are presented in the context of nuclease technology to induce a mutation of the exon 1 of
MHC by APCs. In order for the T cells to be activated, they rag1 in Dahl rats that resulted in deletion of immunoreac-
need two signals: first, an antigen in the MHC of the APC tive rag1 protein in the thymus and a significant reduction
that is recognized by a specific TCR and second, indepen- of T and B lymphocytes. The mutant Dahl SS rats showed
dent costimulation by B7 ligands (CD80 or CD86) that link amelioration of salt-induced hypertension in association
with CD28 in the T cell. In addition, the clonal expansion of with reduced T-cell infiltration in the kidneys.
activated T cells requires a third signal to proliferate that is
provided by cytokines (42). The generation of memory T The participation of lymphocytes was also examined by
cells requires the interaction of the CD27 molecule in the T Crowley et al. (40) who showed that the scid mice with
lymphocyte with costimulatory molecule CD70 in antigen impaired lymphocyte function responded to angiotensin II
presenting cells and is also a central feature of adaptive with enhanced natriuresis resulting from upregulated renal
immunity. Memory T cells are responsible for the acceler- expression of eNOS and COX-2, and increased generation

of NO and prostaglandins. As a consequence, the scid mice is suppressed by Tregs (330), and Amador et al. (2) showed
had a blunted response to the late (after 5 days) hyperten- that DOCA-salt hypertension is associated with activation
sion induced by angiotensin II infusion. Another important of Th17 cells and downregulation of Treg mRNA in heart
finding in this study (40) was the demonstration that lym- and kidneys. Spironolactone (but not other antihyperten-
phocyte deficiency suppressed pressure-independent heart sive treatment) prevented Th17 activation and increased the
and kidney injury induced by angiotensin II. numbers of Treg cells, and treatment with anti-IL-17A an-
tibody ameliorated hypertension and fibrotic injury in heart
1. T helper (CD4⫹) and T cytotoxic (CD8⫹) cells and kidneys. Therefore, IL-17 is an important factor in
mineralocorticoid-induced hypertension, and an alteration
in the IL-17/ Treg balance plays a role in DOCA-induced
Many studies have shown that cytokines activated in a Th1
hypertension. Similar proinflammatory imbalance has been
response play a role in hypertension, and Treg cells amelio-
found to be caused by tacrolimus and is probably causally
rate hypertension (see later). Therefore, it was widely as-
related to the hypertension observed during treatment with
sumed that CD4⫹ T cells were the key elements in the
this drug (34).
pathogenesis of hypertension. Surprisingly, elegant investi-
gations of Trott et al. (278) showed that CD8⫹ T cells
Two recent studies have simultaneously demonstrated that
played a central role in hypertension. Their comprehensive
a high-salt diet is capable of inducing Th17 cells and pro-
studies included TCR V␤ spectratyping of the CD4⫹ and
duction of IL-17. These investigations demonstrated that
CD8⫹ cells isolated form target organs, adoptive transfer
salt induces SGK1 which is a critical modulator of cellular
of CD4⫹ and CD8⫹ T cells to rag 1 ⫺/⫺ mice, and evalua-
Na transport and NaCl homeostasis. Kleinewietfeld et al.
tion of the response to sodium and volume challenge in
(136) found that salt concentrations in the physiological
CD4⫺/⫺ and CD8⫺/⫺ mice. Since T-cell receptors (TCR) are
range activate the p38 MAPK pathway during cytokine-
necessary for the development of adaptive immunity, the
induced Th17 polarization. The salt-induced p38 MAPK
authors examined the TCR V␤ region looking for a domi-
activation resulted from engaging the tonicity-responsive
nant transcript length that would be indication of clonal
enhancer binding protein (TonEBP/NFAT5) and SGK1.
expansion. In the control mice, as expected, there was a
Wu et al. (312) examined the way by which IL-23 stabilizes
Gaussian distribution of TCR V␤ families. However, in
and reinforces a Th17 response. They found that modest
angiotensin II-infused mice, there was a dominant tran-
increments in salt concentration induce SGK1, promote IL-
script length V␤ 3, 8.1, and 17 families in the CD8⫹T cells
23R expression, and stimulate Th17 differentiation in vitro
present in the kidneys. Deep sequencing of the TCR CD8⫹
and in vivo. They demonstrated that SGK1 deactivates
T cells revealed three clonotypes shared by the majority of
FoxO1, which is a suppressor of IL-23R expression. SGK1
angiotensin II-infused mice and absent in controls. The low
was therefore identified as critical downstream element for
frequency of unique clonotypes in the hypertensive kidney
regulating IL23R expression and, thereby, stabilization of
suggested that a group of clones is first activated and, as
Th17. Both papers show how a high-salt diet may induce
inflammation develops and new neoantigens are originated,
IL-17, thereby suggesting a direct link between autoimmu-
a different group of clones is added. The role of CD4⫹ and
nity and salt-driven hypertension.
CD8⫹ cells was studied evaluating the blood pressure re-
sponse to angiotensin II and DOCA-salt in CD4⫺/⫺ and
More recently, Norlander et al. (193) found IL-17 defi-
CD8⫺/⫺ mice. Wild-type and CD4⫺/⫺ mice responded with
ciency suppressed angiotensin-induced activation of so-
similar hypertension and retained sodium and water when
dium-chloride cotransporter and the epithelial sodium
infused with angiotensin II. In contrast, CD8⫺/⫺ mice did
channel in the distal tubule. Interestingly, they also found
not and had a blunted hypertension. Then, the blood pres-
that distal tubular cells produce IL-17 and showed that
sure response to angiotensin of rag 1⫺/⫺ mouse, without
IL-17 deficiency protected from glomerular and tubular
lymphocytes, was evaluated. As in previous studies (90), rag
injury caused by angiotensin II.
1⫺/⫺ mouse had a diminished hypertensive response. Adop-
tive transfer of CD4⫹ T cells did not modify the blunted
3. Regulatory T cells
blood pressure response, while adoptive transfer of CD8⫹
T cells resulted in a full restoration of the angiotensin II-
The role of Tregs in hypertension was evaluated in angio-
induced hypertension. These findings conclusively estab-
tensin-induced and mineralocorticoid-induced hyperten-
lished a role for the CD8⫹ cells in the pathogenesis of
sion. Administration of a single dose or weekly injections
angiotensin-induced hypertension.
of Tregs improve cardiac hypertrophy, electrically in-
duced arrhythmias, endothelial relaxation, oxidative
2. Th17 cells stress, and inflammation in angiotensin II-induced and
mineralocorticoid-induced hypertension, but blood pres-
Th17 cells are involved in adaptive and innate immune sure was not significantly modified (126, 146). However,
responses, and dysregulation of Th17 cells has been associ- mice given a higher dose of Tregs (3 weekly doses of
ated with autoimmune disorders (322). Th17 polarization Tregs for 2 wk) developed a sustained reduction in blood

pressure in association with reduction in immune cell delayed and ameliorated the hypertension of the SPSHR
infiltration (7, 171). The effectiveness of repeated Treg (128). The increment in Treg cells induced by splenic sym-
administration is likely due to repopulation of Tregs that pathetic denervation suggests an additional mechanism for
are depleted by angiotensin-induced apoptosis (7). the hypertension improvement resulting from blockade of
sympathetic activity.
More recently, Majeed et al. (161) used a different strategy
to increase Tregs in angiotensin II-infused mice. They took
B. B Lymphocytes
advantage of investigations that showed that the adminis-
tration of immune complexes of IL-2 and anti-IL-2 mono-
B cells are essential players in adaptive immunity. The role
clonal antibody (IL-2/mAbCD25) result in binding of IL-2
of B lymphocytes in hypertension has been largely unex-
to CD25 expressing cells that induces a selective and rapid
plored because the experiments in the rag 1⫺/⫺ mouse, lack-
expansion of Tregs with anti-inflammatory activity in vivo
ing T and B lymphocytes, showed that only the adoptive
(300). Using optimal doses and molar ratios, they obtained
transfer of T cells of restored the hypertensive response to
a fivefold expansion of the Treg phenotype in spleen with
angiotensin II and DOCA-salt. However, Chan et al. (32)
only minimal changes in CD4⫹ and CD8⫹ T cell numbers. recently showed that angiotensin infusions increase the ac-
IL-2/mAbCD25 was given intraperitoneally for 5 consecu- tivation of B cells and plasma cells in lymphoid tissues and
tive days before angiotensin II infusion and three times induced aortic IgG deposition. Depletion of B cells with the
weekly thereafter. Treatment resulted in a suppression of administration of anti-CD20 antibody, as well as genetic
angiotensin II-induced IL-17 gene expression and reduced deficiency of B cells (BAFF-R⫺/⫺ mice) protected mice from
infiltration and activation of immune cells in the aorta. the chronic pressor effects of angiotensin II. Furthermore,
However, stimulation of natural expansion of the Treg pop- angiotensin II-induced aortic infiltration of macrophages
ulation did not modify angiotensin II-induced hyperten- and CD4⫹ T cells and arterial wall remodeling are sup-
sion. pressed in the BAF-FR⫺/⫺ mice. Since B cells by themselves
do not modify hypertension in the rag1⫺/⫺ mouse (90), the
Mian et al. (182) used a different strategy to evaluate the important experiments of Chan et al. (32) raise a new line of
role of Tregs. They worked with Scurfy mice that are defi- inquiry concerning the participation of B cells in the patho-
cient in Tregs because of a mutation in the FoxP3 gene. genesis of hypertension within a normal (intact) immuno-
These mice die at 4 – 6 wk of age, and the study involved logical environment.
adoptive transfer of T cells from Scurfy and wild-type mice
into rag 1⫺/⫺ mice that lack T and B lymphocytes. The lack
of Treg in the rag 1⫺/⫺ mice that received T cells from C. Natural Killer Cells
Scurfy mice resulted in an exaggerated response to angio-
tensin-induced hypertension and microvascular injury. Natural killer (NK) cells are non-T, non-B lymphocytes
with the capacity for spontaneous or “natural,” antigen-
Other workers have been interested in myeloid-derived sup- independent cytotoxic activity. They are part of the group
pressor cells that are one of the ways by which the immune of innate lymphoid cells that play a central role in the innate
system limits inflammatory injury. The myeloid suppressor immune system (295). Kossmann et al. (138) have shown
cells are a heterogeneous group of immature myeloid cells that there is a mutual activation between NK cells and
that suppress T-cell activation. These cells express myeloid monocytes in angiotensin II-induced hypertension. The role
markers CD11b and Gr1 and have been found to be in- of NK cells in hypertension and vascular remodeling was
creased in the circulation and in the spleen in several models investigated by Taherzadeh et al. (265) who studied a con-
of experimentally induced hypertension. Shah et al. (241) genic strain in which the NK gene complex of the C57BL/6
(Th1 biased) was introduced in the BALB/c (Th2 biased)
showed that treatment with gemcitabine, an immunosup-
background and found that strains that shared the same NK
pressive agent that selectively depletes myeloid-derived sup-
gene complex had similar blood pressure response to
pressor cells, increased the severity of hypertension. Con-
chronic L-NAME-induced hypertension. These studies un-
versely, adoptive transfer of myeloid suppressor cells ame-
derline the role of NK cells in the sensitivity to develop
liorated hypertension (241).
hypertension induced by inhibition of NOS.
Other investigations have uncovered an important interre-
lation between Treg functionality and sympathetic activity. D. Monocytes/Macrophages
The SPSHR have sympathetic overactivity (discussed ear-
lier) and reduced proportions of Tregs cells that precede the Macrophages are always present in vessel walls and in the
development of hypertension. Splenic denervation in- kidney in hypertension. They are involved in innate immu-
creased the Tregs in spleen and in peripheral blood in ap- nity and participate in adaptive immunity acting as antigen-
proximately the same proportion as did the administration presenting cells (APC). Macrophages are closely related to
of the IL-2/mAbCD25 immune complex (see before) and the dendritic cells, and several classifications of macro-

phages are presently in use. One classification uses the tory effects and stimulates M1 macrophages and suppress
LysM marker to separate tissue resident macrophages and the activation of M2 macrophages (17).
inflammatory macrophages. Another and more common
classification differentiates M1 and M2 macrophage sub-
types. The M1 subtype is proinflammatory and is activated E. Dendritic Cells
when exposed to IFN-␥ and TNF-␣. The M2 macrophages
are anti-inflammatory and play an important role in salt Dendritic cells (DCs) are immunocompetent cells closely
and water homeostasis. Investigations without selective de- related to the macrophages. The central function of the DC
pletion of M1 or M2 macrophages are difficult to interpret is to accept antigenic molecules, process them to peptides,
because results may respond to unidentified alteration of migrate to lymphoid organs, and present them in the con-
their balance. Moreover, there is a continuum between the text of MHC to T cells with the receptor that recognizes the
M1 and M2 cell types, and a clear polarization of M1 and specific peptide. Recent investigations indicate that in spe-
cific areas, such as the kidney, DCs have intravascular pro-
M2 macrophages is often impossible.
cesses that may capture antigens and direct T-cell migra-
tion into the tissues (319). Intracellular antigens are pro-
Some studies have evaluated the effects of suppressing mac-
cessed in the proteosome and presented by the MHC
rophage infiltration in the tissues by inhibiting monocyte
class I to CD8⫹ T cells, and extracellular antigens pro-
chemoattractant protein (MCP-1) or blocking the MCP-1
cessed in the lysosome are presented in MHC class II to
receptor C-C chemokine receptor 2 (CCR2). With the use of CD4⫹ T cells. Extracellular antigens may also be pre-
this strategy, reduction in macrophage infiltration and re- sented to CD8⫹ T cells via MHC I by cross presentation.
duction in blood pressure were observed in angiotensin II- There are several subtypes of DCs that preferentially ac-
induced (67, 109) and DOCA-salt hypertension (31). Other tivate CD4⫹ or CD8⫹ T cells. The kidneys have an ex-
investigators studied the osteopetrotic mice (Op/Op) that tensive net of DC especially in tubulointerstitium areas,
are deficient in macrophage colony-stimulating factor and only 5% of them belong to the CD8-like subtype
(m-CSF). They found that the Op/Op mice were protected (302). Selective depletion of DCs is not possible, and
from angiotensin II and DOCA-salt hypertension and therefore, studies examining antigen presentation are fo-
showed less endothelial dysfunction, arterial remodeling, cused on suppression of stimulation signals in antigen
and oxidative stress than the control heterozygous (Op-/⫹) recognition (see sect. VII).
and wild-type mice (48). More recently, elegant investiga-
tions by Wenzel et al. (304) used the cre-lox technology to
induce the diphtheria toxin receptor in LysM-positive mac- V. CYTOKINES IN EXPERIMENTAL
rophages. The subsequent administration of low-dose diph- HYPERTENSION
theria toxin-depleted myelomonocytic cells reduced the
number of circulating monocytes and of macrophages infil- Cytokines that are particularly relevant to hypertension are
trating vascular walls. This treatment corrected the hyper- produced by T cells, B cells, mast cells, macrophages, and
tension, vascular dysfunction, and oxidative stress induced DCs. Studies focusing on specific cytokines in experimental
by angiotensin II infusion. Adoptive transfer of normal models of hypertension are shown in TABLE 2. Several con-
LysM-positive cells restored the angiotensin II-induced ef- siderations are important. First, it should be kept in mind
fects and hypertension. that not only the individual values of the cytokines but also
their balance is important. For example, angiotensin-in-
duced hypertensive renal damage is associated with increase
In addition to the proinflammatory characteristics of the
in Th1 cytokine INF-␥ and reduction in Th2 cytokine IL-4
M1 macrophage, a series of investigations have highlighted
(242). The T-bet deficient mice are unable to produce a
the role of M2 macrophages in sodium and water homeo-
Th1 response, and Zhang et al. (327) showed in the T-
stasis. Initial observations from Titze’s group showed that
bet⫺/⫺ mice that Th1 proinflammatory response was nec-
regions of the dermis serve as a site of water free sodium essary for angiotensin II-induced renal injury but not for
storage (275). Subsequent investigations demonstrated that hypertension. It is also important to recognize that the
interstitial hypertonicity stimulates tonicity-responsive en- antihypertensive result of suppressing a specific cytokine
hancer binding protein (TONEBP) production by the mac- may depend on the experimental model used in the inves-
rophages. TONEBP-stimulated overproduction of VEGF-C tigation. For instance, as depicted in TABLE 2, DOCA-salt
drives lymphangiogenesis in the dermis (158). Depletion of hypertension is unmodified by TNF-␣, IL-6, or IL-17
macrophages, depletion of TONEBP, blockade of vascular deficiency which is in contrast to the amelioration ob-
endothelial growth factor (VEGF) receptor or deletion of served in of angiotensin II-induced hypertension. Finally,
VEGF resulted in salt-sensitive hypertension, demonstrat- cytokines have frequently overlapping functions, which
ing that the macrophage-orchestrated system attenuates the presents a challenge in studies that target individual cy-
hypertensive response to sodium retention (306). More re- tokines to evaluate their role in hypertension and tissue
cent studies demonstrated that high salt has a proinflamma- injury (39). All these circumstances are responsible for

Table 2. Effects of suppressing individual cytokines in experimental models of hypertension

Treatment/Immune
Cytokine Hypertension Model Deficiency Results Reference Nos.
IFN-␥ ANG II infusion IFN-␥⫺/⫺ Hypertension ameliorated (SBP: WT ⫽ 170 mmHg; 125
IFN-␥⫺/⫺ ⫽ 148 mmHg)
ANG II infusion IFN-␥ R⫺/⫺ Injury improved, hypertension unchanged 164
TNF-␣ ANG II infusion TNF-␣⫺/⫺ Hypertension ameliorated (MAP: WT ⫽ 151 252
mmHg; TNF-␣⫺/⫺ ⫽ 113 mmHg)
TNF-␣⫺/⫺ Hypertension ameliorated (MAP: WT ⫽ 183 326
mmHg; TNF-␣⫺/⫺ ⫽ 166 mmHg)
dTGF Etanercept Injury improved, hypertension unchanged 186
DOCA-salt Etanercept Injury improved, hypertension unchanged 66
RANTES ANG II infusion RANTES⫺/⫺ Suppressed perivascular immune infiltration, 183
improved endothelial dysfunction, hypertension
unchanged
IL-1 ANG II infusion IL-1r⫺/⫺ mice Sustained (late) hypertension improved (MAP: 328
WT ⫽ 180 mmHg; IL-1r⫺/⫺ ⫽ 165 mmHg)
IL-4 NZBF1 rats Anti-IL-4 antibodies Hypertension ameliorated (MAP: not treated ⫽ 87 285
mmHg; treated ⫽ 68 mmHg)
IL-6 ANG II infusion IL-6⫺/⫺ mice Hypertension ameliorated (MAP: WT ⫽ 160 147
mmHg; IL-6⫺/⫺ ⫽ 134 mmHg)
DOCA-salt IL-6⫺/⫺ mice Hypertension unchanged 256
Cold-induced hypertension IL-6 knockdown Hypertension improved (MAP: WT ⫽ 140 mmHg; 38
IL-6 deficient ⫽ 120 mmHg)
IL-10 ANG II infusion IL-10⫺/⫺ mice Increased ROS and vascular dysfunction, 55
hypertension unchanged
DOCA-salt treated Injections of IL-10 Hypertension improved (SBP: DSP ⫽ 135 mmHg; 274
pregnant (DSP) rats DSP⫹IL-10 ⫽ 115 mmHg), endothelial
dysfunction improved
IL-17 ANG II infusion IL 17⫺/⫺ mice Late (⬎2 wk) hypertension ameliorated (MAP: 160
WT ⫽ 150 mmHg; IL 17⫺/⫺ ⫽ 128 mmHg)
DOCA-salt Anti-IL-17 Hypertension ameliorated (SBP: not treated ⫽ 150 2
antibodies mmHg; treated ⫽ 123 mmHg), mineralocorticoid
receptor modulates inflammation
DOCA-salt ⫹ANG II IL 17⫺/⫺ mice Hypertension unmodified/injury worse 139
IL-17 administration C57BL/6 mice Blood pressure increment mediated by Rho-kinase 192
SBP, systolic blood pressure; MAP, mean arterial pressure; WT, wild type with the corresponding hypertension model. See text for other
definitions.
the variability in the amelioration of hypertension attrib- B. TNF-␣

uted to suppression of specific cytokines. The reduction
in blood pressure in TABLE 2 ranges from 19% (160) to TNF-␣ belongs to the tumor necrosis factor superfamily. It
no significant antihypertensive effect (55, 66, 139, 164, is produced by macrophages, NK cells, and T cells and has
183, 186, 256). two receptors: CD120a and CD120b. TNF-␣ activates en-
dothelial cells and neutrophils and causes fever and catab-
olism of fat and muscle. Studies examining the role of
A. IFN-␥ TNF-␣ in hypertension have used etanercept or the TNF-
␣⫺/⫺ mouse. Etanercept administration in the dTDF rats
IFN-␥ is a member of the type II cytokine family that is (186) and in DOCA-salt hypertension failed to modify the
produced by T cells. It has two receptors (IFNGR1 and blood pressure levels despite the reduction in albuminuria,
IFNGR2) and induces polarization to the Th1 phenotype cortical NF␬B activity, and cell adhesion molecules (66). In
and activation of macrophages and B cells. IFN-␥ is crit- contrast, TNF␣⫺/⫺ mice have increased eNOS production
ical for the development of renal injury induced by an- and were protected from developing hypertension and from
giotensin II infusion in studies done with IFN-␥⫺/⫺ and the sodium and water retention induced by 2 wk of angio-
IFN-␥R⫺/⫺ mice. Nevertheless, hypertension was either tensin infusion (252, 326). Intrarenal TNF-␣ is increased by
unmodified (164) or improved in association with sup- a high-salt diet in the Dahl SS rat, and administration of
pressed renal sodium transporter activation (125). intrarenal etanercept improved SS hypertension and renal

injury (104). Since TNF-␣ reduces renal blood flow and addition, IL-2 signals are essential for the generation and
inhibits the sodium potassium 2-chloride (NKCC2) trans- survival of Tregs. In turn, Tregs regulate IL-2 availability by
porter, Ryan (228) has noted that blood pressure effects of directly inhibiting IL-2 production, as well as by consump-
TNF-␣ likely depend on the balance between vasoconstriction of IL-2 and by blocking CD80/86 costimulation (50).
tion and natriuretic activities. Therefore, IL-2 is a key player in the development of both
effector T-cell and regulatory T-cell responses. The admin-
istration of IL-2 in doses ranging from 5,000 to 100,000
C. CCL5 (RANTES) units/kg to SHR (206, 282) and Dahl SS rats (82, 110) was
found to ameliorate hypertension (110, 282) or to have no
CCL5 is a chemoattractant for inflammatory cells that is effect on blood pressure (82, 206). Effector T cells and
produced by T cells, resident vascular cells, and adipose Tregs were not examined in these early studies, and it seems
tissue. It has three receptors (CCR1, CCR3, and CCR5). likely that the complex interactions of IL-2, resulting in
CCL5⫺/⫺ mice have suppressed T-cell infiltration in either expansion or suppression of immune reactivity, are
perivascular tissue and less endothelial dysfunction follow- the explanation, at least in part, for the discrepancies in
ing angiotensin II infusion. These effects likely result from a experimental studies.
diminished infiltration of IFN-␥ producing T cells (183).
G. IL-4
D. TGF-␤
IL-4 is a member of the type I cytokine family produced
TGF-␤ is produced mostly by Tregs and macrophages. It
mainly by CD4⫹ T cells and mast cells. IL-4 has two recep-
has three receptors (TGF-␤R1, R2, and R3), stimulates col-
tors (CD124 and CD132) and mediates the differentiation
lagen production by fibroblasts, and inhibits proliferation
to the Th2 phenotype. IL-4 production is suppressed in
and activation of T cells, B cells, and macrophages. TGF-␤
angiotensin II-induced hypertension (242), but to our
is stimulated in SS hypertension, and reduction of TGF-␤
knowledge, the only investigations of the role of IL-4 were
improves several models of experimental glomerulonephri-
done in female NZBW rats by van Heuven et al. (285) who
tis. Administration of anti-TGF-␤ antibodies resulted in
showed that intraperitoneal administration of anti-IL-4 an-
amelioration of salt induced hypertension in the Dahl SS rat
tibody at 6, 8, and 10 wk of age suppressed hypertension in
in association with a reduction in renal and cardiac fibrosis
the NZBW rats.
(44, 187).
E. IL-1 H. IL-6
IL-1 is a member of the IL-1 cytokine family that is pro- IL-6 is a member of type I cytokine family produced by
duced by macrophages, DCs, fibroblasts, endothelial cells, macrophages, endothelial cells, and T cells. It has two re-
keratinocytes, and hepatocytes. IL-1 induces activation of ceptors (CD126 and CD130) and induces proliferation of B
endothelial cells, fever, and synthesis of acute-phase pro- cells and acute-phase protein synthesis. Since IL-6 is in-
teins. IL-1 has two isoforms, IL-1␣ and IL-1␤, and both creased in plasma by angiotensin II infusions, Brands’group
bind a single receptor (IL-1r). Both isoforms of IL-1 are (147, 256) studied IL-6⫺/⫺ mice to establish the role played
increased in the kidney in angiotensin II-induced hyperten- by IL-6 in angiotensin II-induced hypertension. In a series of
sion (40), and deficiency of IL-1r ameliorates the hyperten- elegant studies they showed that the increment in IL-6 re-
sion resulting from 3 wk of angiotensin II infusion (328). quired the presence of aldosterone and hypertension in-
The attenuation of hypertension in the IL-1r⫺/⫺ mice results duced by 800 ng·kg⫺1·min⫺1 of angiotensin II (but not
from increased natriuresis due to absence of angiotensin higher doses) was prevented in the IL-6⫺/⫺ mice, while renal
II-induced hyperactivity of the NKCC2 transporter and to vasoconstriction was unaffected. Angiotensin II-induced
elevated NO levels due to preferential differentiation of phosphorylation of JAK2 and signal STAT 3 were com-
immature Ly6C⫹Ly6G⫹ myeloid cells to the NO-produc- pletely suppressed in the IL-6⫺/⫺ mice (22). Superoxide gen-
ing Ly6C⫹Ly6G- macrophage phenotype (328). eration, vascular remodeling, and endothelial dysfunction
induced by angiotensin II are all dependent on IL-6 gener-
ation (234). In more recent studies it has been shown that
F. IL-2 administration of IL-6 neutralizing antibody attenuated SS
hypertension, renal inflammation, and injury in the Dahl SS
IL-2 is member of the type I family of cytokines. It is se- rat (94). IL-6 is produced not only in T cells and macro-
creted by T cells activated by TCR-antigen presenting cell phages, but also in cells that play a role in hemodynamic
interactions and additionally costimulated via CD80/ physiology, such as endothelial cells (84), vascular smooth
CD86. IL-2 drives the proliferation of effector T cells. Pro- muscle cells (91), and sympathetic nerves (168); therefore,
liferating T cells deprived of IL-2 undergo apoptosis. In blood pressure-lowering effects resulting from suppression

of IL-6 may result, at least in part, from effects other than more than 30 genes, a value several times higher than what
immune modulation. was obtained with TNF-␣ alone. Despite the synergy of
TNF ␣ and IL-17 in the modulation of proinflammatory
An important issue is whether IL-6 plays a role in the phys- genes, the endothelial vascular dysfunction induced by
iological increase in angiotensin II levels. This appears un- IL-17 requires no additional cooperation because IL-17
likely since during a low-salt diet IL-6 levels are not in- causes impairment of NO production due to suppressed
creased and JAK2 is not required to maintain blood pres- eNOS activity (160). Nguyen et al. (192) demonstrated that
sure (22, 30). IL-17 increases phosphorylation of the inhibitory eNOS
residue threonine 495 (eNOS Thr495). Of the various ki-
nases known to activate eNOS Thr495, only the Rho-ki-
I. IL-10 nase activator was responsible for IL-17-induced depres-
sion of the vascular relaxation response. Administration of
IL-10 is a member of type II cytokine family that has anti- IL-17 increased blood pressure that was prevented by an
inflammatory activity. It is produced by monocytes, Th2 inhibitor of Rho-kinase.
lymphocytes, mast cells, subsets of B cells, and Tregs. IL-10
has two receptors: CD210 (IL-10R␣) and IL-10R␤. In ex- Recent investigations have added complexity to the role
perimental preeclampsia, IL-10 administration ameliorates played by IL-17 in the development of inflammation. In a
hypertension and albuminuria (274), and IL-10 deficiency model of hypertension that combines DOCA-salt and an-
aggravates angiotensin II-induced endothelial dysfunction giotensin II, Krebs et al. (139) found that, contrary to their
and superoxide production (55). expectations, deficiency in IL-17/IL-23 axis did not modify
the hypertension and actually worsened the renal and car-
The role played by immunosuppressive cytokines produced diac injury. There is no explanation for these findings at the
by Tregs has been shown in studies of a consomic strain of present time, and the authors (139) raised the possibility of
rats (SSBN2) that have chromosome 2 of normotensive a biphasic response to IL-17 that would confer protection
Brown Norway rats transferred to the genome of hyperten- early in hypertensive disease and cause aggravation in more
sive salt-sensitive Dahl rats (293). SSBN2 rats have in- advances stages.
creased expression of FoxP3, TGF-␤, and IL-10 and a re-
duced blood pressure response to high-salt diet.
VI. INNATE IMMUNITY IN HYPERTENSION
J. IL-17 Several investigations have studied the role played by the

NLRP3 inflammasome in experimental models of hyperten-
The IL-17 family of cytokines comprises six members (A, B, sion (FIGURE 1).
C, D, E and F) of which IL-17A is the prototype. It is
produced by the T helper lymphocyte subtype Th17 and
also by immune activation of DCs, macrophages, natural A. Toll-like Receptors in Hypertension
killer cells, CD8⫹ cells, and gamma-delta T cells. Interest-
ingly, gamma/delta T cells are the major source of IL-17 in The associations of TLRs and inflammation in relation to
the inflammatory damage induced by angiotensin II infu- hypertension have been recently reviewed (177). Activation
sions, and its production is regulated by monocyte-derived of TLR in models of hypertension was first suggested by
IL-1␤ (150). studies demonstrating that TLR4 is increased in the kidneys
of SHR and by the finding that cytokine production by
IL-17 facilitates the infiltration of inflammatory cells in tis- splenocytes from SHR rats is increased following stimula-
sues by the induction of adhesion molecules and chemo- tion of TLR 7/8 or 9. Furthermore, splenocytes of the SHR
kines and has been implicated in the pathogenesis of auto- treated with TLR ligands showed an enhanced cytokine
immune diseases (133). Madhur et al. (160) found that production in the presence of nicotine (an ACh agonist), in
angiotensin II infusions caused a severalfold increment of contrast to the reduction observed in the splenocytes from
IL-17 in circulating T cells, accumulation of IL-17 protein control WKY rats (93). Direct evidence of the role of TLR4
in the medial layer of thoracic aorta, and vascular dysfunc- in hypertension was later shown by the ability of anti-TLR4
tion. Similar results were not observed in the IL-17⫺/⫺ antibody treatment to ameliorate hypertension in the SHR
mouse injected with angiotensin II. Deficiency in IL-17 did (20) and by the failure of TLR4⫺/⫺ mice to develop
not modify the initial increase in blood pressure induced by L-NAME-induced hypertension (247). The importance of
angiotensin II infusions but significantly ameliorated the TLRs in specific areas of the brain is suggested by the dem-
sustained hypertension observed after 2 wk. Interestingly, onstration that TLR4 is upregulated in the paraventricular
gene array studies made in human aortic smooth muscle nucleus of the hypothalamus in the SHR, but not in the
cells revealed that IL-17 by itself induced little gene changes, normotensive WKY rats. Furthermore, injection of a spe-
but in association with TNF-␣ modulated the expression of cific TLR4 blocker to this brain area lowered blood pres-

DAMPs
TLR4 P2x7r
1 2
ATP
Signal 1 Signal 2
K+
ROS
IκB
NLRP3 PYD NACHT
p50 p65
PYD
ASC 4
CARD
p20/p10 Lysosome
Procaspase CARD
3 Microcrystals
Caspase
NFκB
5
Pro-IL-1β IL-1β
Pro-IL-18 IL-18
FIGURE 1. Participation of the NLRP3 inflammasome in the pathogenesis of experimental hypertension. 1)

Suppression or deficiency of TLR4 ameliorates or prevents hypertension (20, 46, 247). 2) Inactivation or
deficiency of the P2x7 receptor ameliorates hypertension in the Dahl SS rat (120). 3) Suppression of NF␬B
activation ameliorates hypertension in SHR (218), Fawn Hooded rat (137), and the dTGF rat (185). 4)
Deficiency of ASC ameliorates DOCA-salt hypertension (140). 5) NLRP3 inflammasome components overex-
pressed in the SHR (see FIGURE 2) and inhibition of inflammasome activation ameliorate DOCA-salt hyper-
tension (140).
sure; reduced mRNA and protein abundance of TNF-␣, proves the blood pressure in adolescent patients with hyper-
IL-1␤, and inducible NOS; and suppressed NF␬B activity in tension (68). It is possible that the activation of specific
SHR (46). urate transporters may increase intracellular urate and for-
mation of microcrystals. It remains to be determined if mi-
Hypertension-related DAMPs are capable of activating crocrystal-induced inflammasome activation represents a
TLR2 and TLR4 signaling. These include angiotensin mechanism of pathogenic importance in essential hyperten-
(119), C-reactive protein (CRP) (151), uric acid (153), and sion.
heat shock proteins 60 (49) and 70 (4).
Oxidative stress has been repeatedly shown to play a role in
The activation of TLR4 and TLR2 in essential hypertension vascular dysfunction and hypertension (277, 307), and ex-
is discussed later. cessive production of reactive oxygen species (ROS) plays a
central role in driving signal I in the process of activation of
B. Activators of the Inflammasome in the inflammasome. Experts have argued that ROS is likely
Hypertension the common signal for inflammasome activation (280) that
is likely situated upstream of NLRP3 induction (10). Over-
Elements potentially responsible for activation of the in- expression of TLRs resulting from excess generation of
flammasome in hypertension include both soluble (315) ROS in complicated pregnancies has been proposed to be a
and crystalline (165) urate, reactive oxygen radicals, and factor in the adult development of hypertension (269).
ATP-induced activation of the P2x7 receptor.
Extracellular ATP acting at P2X7 receptor is a stimulus for
Monosodium urate crystals are recognized danger signals NLRP3 inflammasome activation. The P2X7 receptor is an
of stressed cells that are capable of activating the NLRP3 ion-gated channel that generates K⫹ efflux when activated
inflammasome (108, 165). Mazzali et al. (176) showed that and recruits the pore-forming protein pannexin-1 to the
the induction of hyperuricemia resulted in hypertension in plasma membrane. Potassium efflux triggers inflammasome
rats. Reducing the levels of uric acid with allopurinol im- activation (216).

Angiotensin II infusion induces overexpression of P2X7 their activity. These receptors are expressed in lymphocytes,
(296) and inactivation or suppression of the P2X7 receptor monocytes, vascular endothelial cells, vascular smooth
as well as ameliorates the vicious circle of inflammation and muscle cells, and renal tubular epithelial cells. The receptor-
SS hypertension in the Dahl rat (120). ligand binding recruits accessory proteins and adaptor mol-
ecules that, in turn, activate signaling pathways, transcrip-
C. Inflammasome Components in tion factors such as NF-␬B and AP-1, and downstream pro-
inflammatory cytokines.
Hypertension
NLRP3 inflammasome is activated in the SHR. FIGURE 2 In addition to proinflamatory activity, IL-1␤ and IL-18
compares the protein abundance of the components of the have direct effects on the vessels that may contribute to
NLRP3 inflammasome in SHR with control normotensive hypertension. Rat resistance arteries incubated with IL-1␤
WKY at 40 wk of age. The involvement of the inflam- have increased generation of superoxide and impaired
masome in the pathogenesis of hypertension has been ACh-induced vasodilatation that can be reversed partially
strongly suggested by several studies that have reported that with SOD (121). IL-18 induces proliferation and migration
blocking inflammasome components ameliorates hyperten- of vascular smooth muscle cells also driven by ROS over-
sion in animal models (TABLE 3). production (284).
The binding of inflammasome end products, IL-1␤ and IL- The activation of innate immunity in the SPSHR has been
18, to their specific receptors, IL-1 type 1 receptor (IL-1RI) suggested by the demonstration of increased plasma levels
and the IL-18 receptor ␣ chain (IL-18R␣), is critical for of the IL-1␤ in association with gene overexpression of
WKY SHR
kDa
NLRP3 116
ASC 22
Procaspase 45
Caspase 20
IL-1β 31
IL-18 18
β-Actin 42
NLRP3 ASC Procaspase

0.8 1.2 1.0
1.0
* *
0.6 * 0.8
Relative O.D.
Relative O.D.
Relative O.D.
0.8
0.6
0.4 0.6
0.4
0.4
0.2
0.2
0.2
0.0 0.0 0.0

WKY SHR WKY SHR WKY SHR
Caspase IL-1β IL-18

0.8 0.8 2.0 *
* *
1.5
Relative O.D.
0.6 0.6
Relative O.D.
Relative O.D.
0.4 0.4 1.0
0.2 0.2 0.5
0.0 0.0 0.0
WKY SHR WKY SHR WKY SHR

FIGURE 2. NLRP3 inflammasome components are increased in the kidney of SHR. Relative abundance of
NLRP3, ASC, procaspase, caspase, IL-1␤, and IL-18 in 40-wk-old SHR and normotensive WKY rats. See text
for definitions.

Table 3. Results of interventions in mechanisms of the innate immunity in experimental models of hypertension
Experimental Model Intervention Results Reference Nos.
SHR Anti-TLR4 Hypertension ameliorated (MAP: not treated ⫽ 160 mmHg; 20

treated ⫽ 140 mmHg), reduced vascular contractility
Brain (PVN) blockade of Hypertension ameliorated (MAP: not treated ⫽ 170 mmHg; 46
TLR4 treated ⫽ 142 mmHg), cardiac hypertrophy ameliorated,
reduction of HMGB1
SPSHR IL-1␤ administration Increase in stroke incidence, blood pressure not modified 35
Dahl SS P2X7 receptor antagonist Amelioration of SS hypertension, (SBP: not treated ⫽ 195 120
mmHg; treated ⫽ 165 mmHg), reduction of inflammation
and albuminuria
ANG II Anti-TLR4 antibody Reduced inflammation in VSMC 119
DOCA-salt C5a receptor antagonist Reduction of heart inflammation and fibrosis, hypertension 116
unchanged
ASC⫺/⫺ Amelioration of hypertension (SBP: WT ⫽ 155 mmHg; 140
ASC ⫺/⫺ ⫽ 140 mmHg), reduced inflammation
Inhibition of inflammasome Amelioration of hypertension (SBP: NT ⫽ 160 mmHg; 140
(MCC960) Treated ⫽ 140 mmHg), reduced Inflammation
L-NAME TLR4⫺/⫺ Amelioration of hypertension (MAP: WT ⫽ 125 mmHg; 247
TLR4⫺/⫺ ⫽ 100 mmHg), reduction in arterial
contractility, reduced inflammation
Unilateral uretheral C3⫺/⫺ Amelioration of hypertension (SBP: WT ⫽ 120 mmHg; 329
obstruction C3⫺/⫺ ⫽ 105 mmHg), reduction in intrarenal ANG II,
reduction in EMT
The majority experimental interventions on elements of innate immunity ameliorate hypertension. TLR, Toll-like receptor, PVN, paraventricular
nuclei; ASC, adapter protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; EMT, epithelial
mesenchymal transition; SS, salt sensitive; SBP, systolic blood pressure; MAP, mean arterial pressure; WT, wild type receiving the corre-
sponding hypertensive treatment.
IL-1␤, IL-1 receptors, and caspase-1. The administration of phylotoxins, opsonins and the membrane attack complex,
IL-1␤ using an osmotic pump increased hypertension and that are responsible for the major effects of the complement
the incidence of stroke (35). system. Complement is activated early in the dTGF rat
(240), but only a few studies have examined the role played
As will be discussed later, circulating levels of IL-1␤ (45), by the complement system in hypertension. In DOCA-salt
IL-18 (214), and IL-1 receptor (IL-1Ra) (207) are increased hypertension, treatment with a C5a receptor antagonist im-
in hypertensive patients, and the severity of hypertension is proved cardiac remodeling but did not modify blood pres-
correlated with the levels of IL-18 (214). The possible roles sure. Zhou et al. (329) studied the model of unilateral ure-
of endogenous antagonists of IL-1 receptor (3) and of IL-33, teral obstruction and showed that C3 deficiency prevented
a recently identified cytokine with anti-inflammatory activ- hypertension and renal injury and demonstrated that C3
ity (208) in the pathogenesis of hypertension, are undefined activates the renin-angiotensin system and is central in the
at the present time. development of epithelial-to-mesenchymal transition and
fibrosis in this model.
D. The Complement System
VII. ADAPTIVE IMMUNITY IN
The complement system is a network of plasma- and mem- HYPERTENSION
brane-associated proteins involved in the development of
inflammatory and cytolytic responses and represents a ma- Numerous investigations have established the involvement
jor effector mechanism of the innate and adaptive immunity of several aspects of adaptive immunity in experimental
(60). It is activated by three pathways: the classical path- hypertension (FIGURE 3).
way, activated when C1q binds to an antibody attached to
an antigen; the lectin pathway, activated when mannose- Vinh et al. (294) focused on costimulatory mechanisms of
binding lectin binds to carbohydrate motifs; and the alter- antigen presentation. They demonstrated that angiotensin
native pathway, activated when C3 undergoes hydrolysis II infusion induces overexpression of CD86 in DCs. Block-
and, in the presence of specific factors, presents additional ade of the B7 costimulatory pathway with CTLA4-IgG or
C3 cleavage. The three pathways result in the formation of by genetic deletion of B7 ligands (CD80 and CD86) ame-
convertases that are responsible for the generation of ana- liorates angiotensin-induced and DOCA-salt hypertension

Blood pressure
vascular tone, Na+ retention,
impaired pressure natriuresis,
impaired vasodilation
Arteries, Kidney Spleen
10 2 3 4
APC APC APC
MHC
B7/CD28
TCR
6
1
SNS-CNS CD4+ T cell
ROS
Inflammation CD8+
Ang II
TNF-α, INFγ,
IgG B cell
IL-2, IL-4,
IL-6, IL-17 Memory
7 T cell
8 5
Treg
FIGURE 3. Adaptive immunity in experimental hypertension. Investigations demonstrating involvement of

adaptive immunity in experimental models of hypertension include evidence that isoketal–modified proteins
(135) and overexpression of HSP70 (25, 111, 211) are potential antigens in hypertension-associated immune
reactivity (1). Dendritic cells process the antigen (135) (2), travel to lymphoid organs (135) (3), and present
it to the TCR in T cells (90, 175) in the context of the MHC (225) in association with costimulatory signals (294)
(4). Memory T cells (5) are developed and stored for inducing accelerated responses to subsequent antigenic
challenge (114, 205) and activation and expansion of effector T cells (6) that result in proinflammatory cytokine
responses (see TABLE 2) and regulatory T cells (7, 126, 146, 161, 182, 241) (7). B-cell activation (8) is
necessary for the development of hypertension when the immune system is intact (32). The CNS-SNS axis is
recruited by oxidative stress (154, 155, 251, 333) involving angiotensin II receptors (100, 244, 251) and
results in SNS-induced stimulation of the release of activated T cells from the spleen (9) (27, 28) and
stimulation of target organ immune infiltration and reactivity (314) (10). APC, antigen presenting cells;
MHC, major histocompatibility complex; TCR, T cell receptor; CNS, central nervous system; SNS, sympa-
thetic nervous system.
(294). Furthermore, the hypertensive response could be re- appearance of circulating CD3⫹T cells, a drastic reduction
stored in the B7⫺/⫺ mice by adoptive transfer of bone mar- of the infiltration of T cells in the kidney and amelioration
row from the wild-type mice. in the SS hypertension and albuminuria.
The critical role of antigen presentation was also demon- Itani et al. (114) explored the generation of memory T cells
strated in the elegant experiments of Rudemiller et al. (225) in angiotensin II and L-NAME models of hypertension to
who focused on CD247 gene that encodes the CD3 ␨ chain, demonstrate the participation of adaptive immunity. Mice
involved in the assembly of the T-cell receptor of antigen given a low dose of angiotensin II (140 ng·kg⫺1·min⫺1) or a
recognition. Population studies in hypertensive patients had high-salt diet do not develop hypertension. However, hy-
revealed an association between high blood pressure and a pertension developed if mice had previously received a high
single polymorphism variant in intron 1 of CD247 (64). dose of angiotensin II (490 ng·kg⫺1·min⫺1) or 2 wk of
This finding led Rudemiller et al. (225) to delete CD247 in L-NAME treatment before the administration of the high-
the genetic background of the Dahl SS rat to examine the salt diet. The development of hypertension in response to
importance of T-cell activation in salt-induced hyperten- secondary subthreshold stimulation in these mice was the
sion. The CD247⫺/⫺ Dahl SS rat had almost complete dis- result of activation of memory T cells demonstrated in the

kidney and in the bone marrow. Mice lacking CD70, high-salt diet after transient exposure to L-NAME (213). In
thereby incapable of generating memory T cells, did not this model, HSP70 is overexpressed in the kidney, and T
develop hypertension on secondary stimulation. Adoptively cells present a clonal CD4 response when exposed to
transferred memory T cells nested in the bone marrow and HSP70. Immune tolerance resulted from the generation of
the spleen of the recipient and expanded in response to IL-10 producing Tregs and was associated with reduced
antigen exposure. renal inflammation and prevention of salt-driven hyperten-
sion. Adoptive transfer of T cells from tolerized rats into
VIII. AUTOIMMUNITY IN EXPERIMENTAL rats with SS hypertension corrected hypertension. In addi-
HYPERTENSION tional experiments, we transfected the kidneys with a plas-
mid-HSP70 construct (pCMVSPORT6-human HSP70) in-
Recent studies have focused on autoantigens of potential jected in both renal veins that were occluded during the
relevance in activating the adaptive immune system in hy- procedure. This procedure led to renal overexpression of
pertension. Pons et al. (211) studied the role of HSP70 in HSP70 and in rats previously sensitized to HSP70 resulted
autoimmune reactivity in SS hypertension. HSPs, and par- in renal inflammation and salt-induced increase in blood
ticularly HSP70, are immunodominant molecules that, in pressure (211).
addition to functioning as chaperones of nascent proteins
and driving the immune response to microorganisms, play a In 2014, Kirabo et al. (135) examined autoimmune phe-
well-recognized role in autoimmunity either by themselves nomena resulting from oxidative stress in hypertension. In
or binding to misfolded proteins (276). HSP70 is overex- their comprehensive studies, they showed that angiotensin
pressed in the kidney of in L-NAME-induced and angioten- II infusion and DOCA-salt administration induce hyperten-
sin-induced hypertension (25, 111), and T cells obtained in sion in association with generation of ROS in dentritic cells.
experimental models of SS hypertension develop a prolifer- Since reduction of the blood pressure with hydralazine did
ative reaction when challenged with HSP70 (205). In the not prevent the generation of ROS, the oxidative stress is
adult SHR, HSP70 and HSP72 are overexpressed in the not caused by the increase in blood pressure. Oxidative
kidney. Furthermore, overexpression of HSP72 is already stress resulted in the formation of ␥-ketoaldehydes (isoket-
present in the SHR at 4 wk of age, before hypertension als) that bind to lysine residues and crosslink proteins that
develops (FIGURE 4). accumulate in DCs resulting in neoantigens. The formation
of isoketal-protein adducts drives DCs to produce IL-6,
Since a specific amino acid sequence in mycobacterial IL-1␤, and IL-23 and to increase costimulatory proteins
HSP70 induces an IL-10 response capable of preventing CD80 and CD86. Activated DCs induced proliferation of T
autoimmune arthritis in rats (212, 303), we used the same cells, especially CD8⫹T cells with the production of IFN-␥
peptide to induce immune tolerance to HSP70 in rats given and IL-17A and hypertension. All these events were sup-
WKY (4wks old) SHR (4 wks old)

WKY
HSP72
HSP70
WKY (40 wks old) SHR (40 wks old)
HSP72
HSP70
β-Actin
HSP72 HSP70 SHR

4 weeks 40 weeks 4 weeks 40 weeks
1.5 1.5
2.5 2.5
** *
Relative O.D.
Relative O.D.
Relative O.D.
Relative O.D.
2.0 2.0
1.0
*
1.0
1.5 1.5
1.0 1.0
0.5 0.5
0.5 0.5
0.0 0.0 0.0 0.0

WKY SHR WKY SHR WKY SHR WKY SHR
FIGURE 4. Relative content of HSP70 and HSP72 in SHR and WKY at 4 and 40 wk of age. SHR are
normotensive at 4 wk of age and have overexpression of HSP72. At 40 wk of age, HSP70 and HSP72 are
overexpressed in the SHR. Histology corresponds to immunoperoxidase staining for HSP70 in WKY and SHR
40 wks of age.

pressed with the administration of the isoketal scavenger Oxidative stress and inflammation support one another.
2-HOBA. Adoptive transfer of DCs activated with isoketals Oxidative stress activates proinflammatory transduction
induced hypertension in wild-type mice but not in rag 1 ⫺/⫺ pathways (JNK, p38 MAPK) and transcription factors
mice that lack T cells. (AP-1 and NF␬B) and is a potent stimulus for lymphocyte
function (157). Conversely, inflammation induces and am-
Subsequent studies done in mice with excessive vascular plifies oxidative stress by the generation of increased
production of ROS by overexpression of NADPH oxidase amounts of ROS that represent a necessary component of
subunit p22(phox) or deletion of SOD have demonstrated innate immunity.
isoketal-protein adducts in aortas, DCs, and macrophages
that are capable of activating T cells. Treatment with tem- Angiotensin II is a third element that interacts with oxida-
pol (SOD mimetic) or 2-HOBA prevented T-cell and den- tive stress and inflammation. All components of the renin-
dritic cell activation, vascular inflammation, and hyperten- angiotensin system (RAS) are present in the kidney. Navar’s
sion (311). These important studies (135, 311) established a group has shown that the intrarenal RAS system is regu-
missing and important link between oxidative stress, adap- lated differently from the circulating RAS and that intrare-
tive immunity, and hypertension. nal RAS activation has a key role in the pathogenesis of
hypertension (190, 191). An example of the independence
of the renal and systemic RAS is the Page (cellophane wrap)
IX. PATHOPHYSIOLOGY OF
kidney model of hypertension in which the plasma angio-
HYPERTENSION INDUCED BY
tensin II is unaltered but the renal angiotensin II is increased
IMMUNITY
in association with interstitial renal inflammation (286). In
SS hypertension, the severity of hypertension is directly cor-
Elevation of the blood pressure is the result of many factors.
related with renal concentration of angiotensin II and in-
The participation of immunity is a consequence of a com-
plex interaction between activated immune cells, oxidative versely correlated with plasma concentration of angiotensin
stress, and angiotensin II activity that drives a low-grade II, which, as expected, is suppressed by a high-salt diet (71).
inflammation in the kidney, arteries, and central nervous While most intrarenal RAS is generated in intrinsic cells in
system. the kidney, 20 – 40% of lymphocytes and macrophages in-
filtrating the kidney stain positive for angiotensin II (FIGURE
5). These findings are consistent in several studies (213,
A. Interactions Between Oxidative Stress, 220, 222) and were unexplained until investigations by
Inflammation, and Angiotensin II Hoch et al. (101) elegantly showed lymphocytes produced
angiotensinogen, angiotensin converting enzyme (ACE),
Oxidative stress, inflammation, and angiotensin II activity and renin and produced angiotensin II that contributed to
are inextricably linked in the pathogenesis of hypertension T-cell activation.
(272, 289, 307). Recent studies have added insight on the
role of mitochondrial oxidative stress in hypertension. The The complex interplay between the immune cells and the
redox activation of CypD, a regulatory subunit of the mi- RAS in hypertension has been highlighted in the studies of
tochondrial permeability transition pore implicated in cell Crowley’s group (41, 325, 327) who demonstrated that the
death, drives the generation of ROS in angiotensin II-in- type of cell expressing AT1r is critically important in hyper-
duced hypertension in cooperation with IL-17. tension induced by angiotensin II. Specifically, bone mar-
row chimeras lacking AT1r had normal baseline blood
CypD deficiency and inhibition of CypD, overexpression of pressure and, surprisingly, presented an augmented blood
mitochondrial SOD2, or scavenging of mitochondrial ROS pressure response to angiotensin II, thereby documenting a
with mitochondria-targeted antioxidants are all capable of protective role of AT1r in bone marrow-derived cells
attenuating angiotensin-induced hypertension (57, 59, against the hypertensive actions of angiotensin II. To con-
112). firm these results, Zhang et al. (327) removed the AT1r
A B
FIGURE 5. Lymphocytes staining positive for angiotensin II
in tubulointerstitial areas of the SHR. Double staining meth-
odology used to demonstrate by indirect immunofluorescence
(A) lymphocytes (fluorescein-labeled CD5 positive cells) ex-
pressing angiotensin II (rhodamine-labeled angiotensin II pos-
itive cells) (B). [From Rodriguez-Iturbe et al. (222).]

from CD4⫹T lymphocytes using the Cre-lox gene targeting AT1r expression in the immune system, may result in
technology. They showed that the CD4⫹ T cells lacking greater benefits than global AT1r blockade in the treatment
AT1r have increased expression of T-bet transcription fac- of progressive renal damage.
tor which drives a Th1 commitment (264), whereas T cells
expressing AT1r have a suppressed Th1 response and pro- B. Renal Inflammation in Hypertension
tect the kidney from angiotensin-induced injury. Suppress-
ing AT1r from LysM expressing macrophages did not mod- The pressure-natriuresis relationship defines a renal adaptive
ify the chronic hypertensive response to angiotensin II but response to maintain sodium balance. Impairment in the pres-
increased tubulointerstitial fibrosis, indicating that the sure-natriuresis response implies that elevation of the blood
AT1r attenuated the expression of M1-type proinflamma- pressure is necessary to induce the natriuresis required to
tory cytokines (325). maintain water and sodium homeostasis (89).
These important studies highlight the independence and In the kidney, the renal infiltration of immune cells in the
complex interrelation of proinflammatory and hemody- SHR precedes the development of hypertension (221). Re-
namic responses to angiotensin II mediated by AT1r. A nal inflammation is associated with impairment in the pres-
large body of experimental and clinical evidence has shown sure-natriuresis response (219), and the intensity of im-
that angiotensin II receptor blockers ameliorate hyperten- mune cell infiltration in the kidneys has been found to be
sive renal damage and kidney disease progression. There- correlated with the severity of hypertension in the SHR
fore, the results of global AT1r blockade are anti-inflam- (222) (FIGURE 6), in SS hypertension (71), and in autopsies
matory. Rudemiller and Crowley (224) have suggested that of patients with hypertension (105). In SS hypertension,
AT1r in nonimmune cells may modify the function of AT1r determinations made at similar (controlled) renal perfusion
in immune cells or, alternatively, that AT1r activation in pressure show that accumulation of immune cells is in-
immune cells would improve renal injury by driving over- versely correlated with fractional sodium excretion (72)
activated leukocytes to apoptosis. At any rate, the findings (FIGURE 6).
of Crowley’s group suggest the possibility that selective sup-
pression of the RAS in the kidney and the cardiovascular Renal inflammation is associated with increased intrarenal
system, in association with preservation or enhancement of angiotensin II activity that plays a major role in the inflam-
A PAS CD68 ANGII B

180 p<0.0001
SBP (mmHg)
160
Control 140
120
50μm
50 μm 50 μm
50 μm 5050
μmμm
100
90 20 40 60 80 100
CD68+CD3 positive cells/mm2
SSHTN
C
1.6 C-NSD
1.4
C-HSD
1.2
MMF
FNaE (%)
1.0
SSHBP
0.8
0.6
0.4 *
MMF
0.2 *
0.0
90 110 130 150

Renal Arterial Pressure (mmHg)
FIGURE 6. Immune cell infiltration in tubulointerstitial areas impairs pressure natriuresis. A: salt-sensitive
hypertension following L-NAME administration (SSHBP) is associated with immune cell infiltration and angio-
tensin positive cells in tubulointerstitial areas that are suppressed with mofetil mycophenolate (MMF) treat-
ment. B: the severity of salt-induced hypertension is directly related to the intensity of immune cells (CD68⫹
and CD3⫹ cells) infiltration. C: pressure natriuresis is impaired in SSHBP. MMF treatment increases pressure
natriuresis in L-NAME-treated rats to the values found in control rats on a high (C-HSD) and normal (C-NSD)
sodium diet. SBP, systolic blood pressure; FNaE, fractional sodium excretion. [Data from Franco et al. (72).]

mation-induced impairment in the pressure-natriuresis (71, tion may trigger the remodeling of the vessel walls and
72). Vascular AT1r are critical for the renal actions of an- thereby contribute to the increased vascular resistance and
giotensin II (249) that include glomerular vasoconstriction, hypertension (233).
upregulation of tubuloglomerular feedback, and stimula-
tion of tubular sodium reabsorption (190).
D. Central and Autonomic Nervous System,
Other elements of the renal RAS system are necessary for Immunity, and Hypertension
the chronic blood pressure responses to angiotensin II. Re-
cent studies in inbred mice deficient in renal ACE have The interrelation between the central nervous system (CNS)
demonstrated that renal ACE is indispensable for the devel- and the immune system depends on the extensive sympa-
opment of sustained hypertension induced by angiotensin thetic innervations existing in lymphoid organs (65). Sev-
infusions and for the SS hypertension resulting from inflam- eral investigations have examined the participation of the
matory injury. Modulation of glomerular filtration rate and CNS in angiotensin II-induced hypertension, and research
activation of proximal and distal tubular sodium transport has centered on the anteroventral third ventricle (AV3V)
require a critical level of local angiotensin II that is not region because this area has a poorly developed blood-brain
obtained in the absence of renal ACE (81, 83). barrier and is capable of responding to angiotensin II (96).
Angiotensin II increases superoxide production in subfor-
Renal inflammation has additional characteristics that have nical organs (332). Deletion of SOD in circumventricular
a negative impact on pressure natriuresis. Asghar et al. (5) organs augments the perivascular infiltration of activated T
have shown that the function of dopamine D1 receptors cells, the sympathetic outflow, and the hypertensive re-
that are involved in urinary sodium excretion is compro- sponse (154). Conversely, reducing oxidative stress by in-
mised by inflammation, and Johnson and Schreiner (122) tracerebral administration of adenovirus encoding for SOD
proposed that loss of peritubular capillaries critically im- (333) or by suppression of p22 (phox) subunit of NADPH
pairs pressure natriuresis. oxidase in the subfornical organ inhibits accumulation of
leukocytes in vascular walls and ameliorates hypertension
(155). These data give strong support for the role of oxida-
C. Vascular Inflammation in Hypertension tive stress in the CNS in the pathogenesis of angiotensin
II-induced hypertension.
A number of studies have demonstrated in experimental
models of hypertension the infiltration of T cells, mono- Angiotensin II directly or by pathways driven by generation
cytes, and DCs in perivascular and adventitia of large and of ROS increases proinflammatory cytokines in the brain
medium-sized vessels (7, 90, 126). IL-6 plays a role in (244), which led Sriramula et al. (251) to examine if the
perivascular immune cell infiltration since RNA interfer- central actions of angiotensin II were mediated by TNF-␣.
ence knockdown of IL-6 ameliorates the lymphocyte and Intracerebroventricular injections of etanercept reversed
macrophage infiltration in the aorta (38). Similar reduction angotensin-induced increments in TNF-␣, IL-6, and IL-1␤;
in angiotensin II-induced perivascular inflammation was suppressed the expression of AT1r; and attenuated hyper-
demonstrated in MAPK2-deficient mice (61). tension (252).
Perivascular inflammation is associated with increased va- AT1r in the CNS are important in other models of hyper-
soconstriction in response to norepinephrine and impair- tension. Targeted deletion of AT1r in the subfornical organ
ment of endothelial-dependent (ACh-induced) vasorelax- results in a blunted hypertensive response to DOCA-salt in
ation (7, 90, 126, 293). The mechanism of periarterial ac- association with reduction in polydipsia, polyuria, and so-
cumulation of immune cells is not completely defined, but dium intake (100).
sympathetic nerve endings are present in these areas and the
central nervous system plays a major role in the activation, Since hypertension is associated with systemic markers of
homing, and infiltration of immune cells in vascular areas inflammation, it is important to define if systemic inflam-
(167). mation may drive pro-hypertensive responses in the CNS.
Wu et al. (309) used intraperitoneal minipumps to infuse
Gratze et al. (85) showed that a functional transcription low dose (1.2 mg·kg⫺1·day⫺1) of lipopolysaccharide for 2
factor Id2 is necessary for angiotensin II-induced hyperten- wk. As a result, blood levels of CRP, TNF-␣, and IL-1␤
sion and organ damage. The Id⫺/⫺ mouse is deficient in increased and hypertension developed. The participation of
DCs, NK cells, and memory CD8⫹ cells, but extensive bone the CNS was demonstrated because these effects were sup-
marrow and kidney transplant experiments suggested that pressed by intracisternal administration of minocycline or
alterations in immune cells, by themselves, were not respon- by the inhibitor of cytokine synthesis pentoxifylline.
sible for angiotensin resistance. Rather, the authors posited
that alterations in the vessel wall were responsible for the The SNS is the major interconnecting pathway linking the
findings in the Id2⫺/⫺ mice (85). The immune cell infiltra- CNS and the immune system (FIGURE 7). Stimulation of

Systemic inflammation (309)

Ang II, ROS (154, 155, 333)
PVR Central nervous system

Cardiac output
T lymphocytes
Renal sodium reabsorption
production of Th1 and FIGURE 7. Participation of the sympa-
Th2 cytokines (65)
thetic nervous system in the immune re-
sponses (key references in parentheses).
Most of the immune-related effects of the
sympathetic nervous system have been iden-
Sympathetic tified using angiotensin infusions. Hemody-
Spleen Macrophages
nervous system namic actions of the sympathetic nervous
mRNA IL-1b, IL-2, IL-6 (78) TLR-mediated system favoring hypertension are included in
PIGF-induced release of production of IL-1β (86) a box. PVP, peripheral vascular resistance;
immune cells (27) PIGF, placental growth factor.
Kidney Dendritic cells
Immune cell Co-stimulation markers

infiltration (314) Bone marrow IL-1, IL-1β, IL-6 (314)
CD4+, CD8+, CD3+ and

CD68+ T cells (78)
the SNS results in an increase in blood pressure due to an More recent studies have added insight to the mechanisms
increase in peripheral vascular resistance, cardiac output, driven by the SNS stimulation that result in activation and
and renal sodium reabsorption. In addition, immune cells release of T cells from the spleen. Extensive investiga-
express adrenoreceptors and may release norepinephrine tions by Carnevale et al. (27) reported that sympathetic
that influences the traffic of lymphocytes and, depending signals stimulate norepinephrine release and placental
on the preexisting state of the stimulated lymphoid cells, growth factor (PIGF, a member of the angiogenesis fam-
induce production of Th1 or Th2 cytokines (65). While ily related to the VEGF) from the spleen. Genetic deletion
adrenergic stimulation increases the TLR-mediated pro- of PIGF completely prevents angiotensin II-induced hy-
duction of proinflammatory cytokines by macrophages pertension, vascular and renal immune cell infiltration,
(86), the sympathetic stimulation of immune cells may and organ damage. Increased PIGF suppresses the ex-
induce both anti-inflammatory or a proinflammatory re- pression of tissue inhibitor of metalloproteinases 3
sponses depending on the perceived requirement of the (Timp3). The suppression of Timp3 is mediated through
occasion (65).
the transcriptional Sirt1-p53 axis and allows costimula-
tion via CD68 of T cells and their migration from the
Changes in immune reactivity resulting from sympathetic
spleen to the vascular walls and the kidney. These com-
nerve discharge have been investigated in the bone marrow
prehensive studies (27) further demonstrated that abla-
and in the spleen because these organs have dense sympa-
tion of the splenic nerve, or the celiac ganglion, or sple-
thetic innervations. Angiotensin II infusion induces a 46%
decrease in bone marrow-derived endothelial progenitor nectomy prevented the influx of pathogenic T cells to
cells (EPC) and a 250% increase in bone marrow-derived target organs, thus showing, first, that sympathetic inner-
inflammatory cells. This proinflammatory modification was vation is a requisite for target organ inflammation and,
corrected by intracerebroventricular administration of mi- second, that immune cells infiltrating target organs are of
tochondria-targeted antioxidant that also ameliorated hy- splenic origin. Reimplantation of the spleen from wild-
pertension. Retrograde labeling of the paraventricular nu- type donors reestablished angiotensin II-induced hyper-
cleus neurons of the brain after injecting the bone marrow tension while reimplantation of spleens from PIGF-defi-
with green fluorescent protein-tagged pseudorabies virus cient donors did not change the resistance to angiotensin
confirmed the brain-bone marrow interaction (124). This II resulting from splenectomy. The role of the Sirt1 was
brain-immune system interaction is also evident by the in- demonstrated because its selective inhibitor Ex-527 and
crease in the mRNA expression of IL-1␤, IL-2, and IL-6 in genetic silencing of Sirt1 in PIGF-deficient splenocytes
the spleen resulting from intracerebroventricular adminis- restored the hypertensive response to angiotensin II.
tration of angiotensin II (78). These elegant studies uncover previously unidentified

roles for the SNS in the immune pathogenesis of hyper- X. IMMUNE REACTIVITY IN PATIENTS
tension. WITH HYPERTENSION
The role of the SNS as a mediator of the renal inflamma-

tion induced by angiotensin II was also studied by Xiao et A. Hypertension in Autoimmune Diseases
al. (314) who showed that denervation of renal arteries
blunts the hypertension induced by angiotensin II and The increased incidence of hypertension in autoimmune
suppresses the immune cell infiltration in the kidneys. diseases is well recognized. In SLE the median age of devel-
Other effects of angiotensin, such as the formation of opment of hypertension is 24 yr (229a). The prevalence of
isoketal-protein adducts in DCs and the expression of hypertension in rheumatoid arthritis is 52–73% (203), in
dermatomyositis/polymyositis is 70% (56), and in systemic
costimulation markers and production of cytokines are
scleroderma with renal involvement is 90% (143). De-
also prevented by renal denervation. DCs have RNA for
spite the accumulated evidence that associates autoim-
␣1D, ␣2A, ␣2B, ␣2C, ␤1, and ␤2 adrenergic receptors.
mune disease and hypertension, the question of a causal
These receptors are downregulated by angiotensin II,
relationship remains unanswered. In NZBW mice that
with the exception of ␤2 adrenoreceptors that are in- have a disease resembling SLE in humans (102, 179),
creased by angiotensin II infusion. However, angioten- Ryan and McLemore (229) found that increase in anti-
sin-induced effects are not mediated by adrenergic ␤2 DNA titers and mean arterial pressure both occurred at
receptors because they are not suppressed in mice lacking 36 wk of age. Hypertension was associated with a shift to
these receptors (314). the right of the pressure natriuresis relationship (169),
and administration of rosiglitazone (an insulin sensitiz-
The parasympathetic nervous system also participates in ing agent that stimulates peroxisome proliferator-acti-
the regulation of the immune reactivity driving anti-in- vated receptors) ameliorated hypertension in association
flammatory responses. T cells express ACh receptors with a reduction in renal immune cell infiltration (291). A
(AChR), and stimulation of the vagus nerve inhibits the reduction of blood pressure was obtained by TNF-␣
secretion of TNF-␣ from the macrophages and reduces blockade with etanercept (290), and administration of
systemic inflammation. The receptor of this ACh-medi- anti-CD20 antibody reduced the formation of autoanti-
ated response to vagal stimulation is the nicotinic AChR bodies, decreased TNF-␣ expression, and ameliorated
alpha7 subunit (299), and the AChR⫺/⫺ mice have in- hypertension (170). While a causal relationship cannot
creased severity in angiotensin II-induced inflammation be definitely established, these investigations strengthen
(148). It is interesting that dysfunctional cholinergic the association between autoimmunity and hypertension
stimulation of the innate immunity has been demon- and strongly suggest that in autoimmune diseases the im-
strated in the SHR. Harwani et al. (93) have shown that mune reactivity plays a key role in the development of hy-
SHR has an inflammatory innate immune response to pertension.
nicotine/cholinergic stimulation. TLR-mediated re-
sponse to nicotine, both in vivo and in splenocytes, re-
B. Immunoglobulins and Inflammatory
sulted in overproduction of IL-6 and IL-1␤ and increase
Markers in Essential Hypertension
in CD161⫹ activated macrophages in the prehyperten-
sive SHR. This contrasts with the pronounced anti-in-
In 1970, Ebringer and Doyle (62) reported that 118 severely
flammatory nicotininc/cholinergic modulation of the in-
hypertensive patients (standing mean blood pressure ⱖ130
nate immune response in the WKY rat. These investiga-
mmHg) had higher levels of serum IgG than 163 age-and
tions raise the intriguing possibility that reverse
sex-matched normotensive blood donors. The authors sug-
modulation of the immune system by the autonomic ner- gested that autoimmune reactivity was driven by vascular
vous system could play a role in the development of ge- damage induced by hypertension. Several subsequent stud-
netic hypertension. ies documented increased IgG levels in patients with essen-
tial hypertension (88, 142, 198). More recent studies have
In a recent paper, Carnevale et al. (28) reported a vagus- analyzed the relationship between markers of inflammation
splenic nerve pathway, mediated by nicotinic cholinergic and blood pressure in patients with essential hypertension.
receptors, that links the brain and spleen. Interestingly, IL-6 levels were found to be significantly associated with
thermoablation of the splenic nerve prevents T-cell egres- blood pressure in a study of healthy men (29). Increasing
sion and protects against hypertension. quartiles of CRP have been reported to be associated with
increasing prevalence of hypertension in a population sur-
The clinical relevance of the wealth of experimental data vey (13) and with blood pressure levels in a case-control
associating hypertension and immunity is supported by study (12). A larger cross-sectional population study that
data obtained in patients with essential hypertension that included 4,813 men and 3,534 women ⱖ20 yr of age ar-
will be discussed in the following sections. rived to similar results: the prevalence of hypertension in-

creased in each one of the increasing quartiles of CRP (258). essential hypertension. Collections of lymphocytes were
Prospective studies in 20,525 normotensive female health found infiltrating interstitial areas in the vast majority of
professionals aged 40 yr or older, followed for a median of biopsies, including in 20% of specimens graded normal or
7.8 yr, demonstrated a linear trend in the association be- with only minor vascular and glomerular changes (grade
tween the levels of CRP and the development of hyperten- 0 –1). Heptinstall (97) also reported lymphocyte infiltration
sion in all prespecified subgroups (238). Since increased in 16 of 37 renal biopsies obtained during sympathecto-
levels of inflammatory markers precede hypertension, in- mies, and Gareau et al. (80) described interstitial nephritis
flammation was not the result of hypertension. The same in 7 of 55 patients and noted that it was impossible by the
authors (239) subsequently did a nested case-control study histological examination of the biopsies to define if the “in-
of 400 women developing hypertension during 10 yr of terstitial nephritis influence the progression to nephroscle-
follow-up in the Women’s Health Study and an equal num- rosis or if it is the cause of hypertension.” Similar interstitial
ber of age-matched normotensive controls. All the partici- lymphocyte infiltrations are observed in protocol biopsies
pants initially had a normal blood pressure. After multivar- taken from hypertensive donors in renal transplantation
iate adjustment, the increased risk of hypertension was (217). Hughson et al. (105) examined autopsied kidneys of
strongly associated with CRP levels and weakly, if at all, 107 African Americans and 87 whites aged 18 to 65 yr. Of
with IL-6. Higher levels of CRP have also been found in them, 59 African Americans and 39 white patients were
prehypertensive individuals (BP ⫽ 120 –139/80 – 89 classified as hypertensive from the chart review. There were
mmHg) (134) and in patients with isolated systolic hyper- no associations between hypertension and glomerular num-
tension (172). Nevertheless, despite an association between ber or birth weight and, therefore, the data did not support
high CRP levels and hypertension, a causal relationship has the notion that a congenital under endowment of nephrons
not been demonstrated. In fact, Smith et al. (246) used a was a common factor in the pathogenesis of essential hy-
Mendelian randomization approach to examine a possible pertension (26, 130). Instead, the data showed a significant
causal relationship analyzing the association of the correlation (P ⬍ 0.001) between immune cell infiltration
1059G/C polymorphism in the human CRP gene with pulse (CD68⫹ cells) and mean arterial pressure. Additional data
pressure and hypertension. The expectation was that a were obtained in seven hypertensive patients by Youn et al.
higher incidence and prevalence of hypertension would be (320) who found significant interstitial infiltration of
found in subjects carrying the polymorphism that results in CD4⫹ and CD8⫹ T cells in association with increased
higher CRP levels. This was not the case, and the work expression in the proximal and distal tubules of I-TAC, one
failed to confirm a causal relationship between CRP and of the CXCR3 chemokines that initiates T cell-driven in-
blood pressure. flammation.
Mirhafez et al. (184) examined the blood levels of 12 cyto-

kines and growth factors in 155 hypertensive and 148 nor- D. Evidence for Innate Immunity in Human
motensive individuals and found that hypertensive patients Hypertension
had higher concentrations of IL-1␣, IL-2, IL-8, VEGF,
IFN-␥, TNF-␣, and MCP-1 and lower levels of IL-10. No Marketou et al. (163) investigated gene expression of TLR4
differences were found in IL-4, IL-6, and IL-1␤ levels. Other and TLR2 in the peripheral blood monocytes of 43 nondi-
studies have found that IL-6 and TNF-␣ blood concentra- abetic patients with grade I or II hypertension and in 16
tions were high in hypertensive patients (14, 76, 115, 118) normotensive controls. Despite the small sample number,
or similar in hypertensive and normotensive subjects (207, they found increased mRNA levels of TLR4 in hypertensive
243). Prospective studies fail to find a significant association patients. They also found that intense (but not standard)
between IL-6 levels and the risk of hypertension (239). blood pressure treatment reduced TLR4 and TLR2 mRNA
Taken together, these studies have a reasonable agreement levels.
in the association between high CRP values and prevalence
and incidence of hypertension. Other inflammatory mark- Dalekos et al. (45) compared the serum levels of IL-1␤ of 28
ers have given less consistent results. untreated patients with essential hypertension, 31 normo-
tensive patients with familial hypercholesterolemia, and 35
healthy controls. Hypertensive patients had serum levels of
C. Renal Infiltration of Immune Cells in IL-1␤ that were three to five times higher than the other two
Human Hypertension groups. Circulating monocytes isolated from hypertensive
patients have exaggerated IL-␤ production in response to
The renal infiltration of immune cells in patients with essen- angiotensin II and lipopolysaccharide stimulation, both at
tial hypertension has been known for a long time. In 1958, the protein and at the mRNA level, suggesting a state of
Sommers et al. (248) published a seminal paper detailing the inflammasome preactivation (58).
renal biopsy findings of 1,346 subjects with essential hyper-
tension in whom tissues were obtained during sympathec- IL-18 has also been studied in essential hypertension. While
tomies that were, at the time, an accepted treatment of the PRIME European study found no difference in circulat-

ing IL-18 levels in patients with and without hypertension F. Autoantigens in Essential Hypertension
(18), the MONICA/KORA in Germany (270), the CUDAS
study in Perth (106), and the Dallas Heart study (334) all The generation of autoantigens in arteries of hypertensive
found that hypertensive patients had higher levels of IL-18. patients (75, 199) and their association with vascular com-
plications (141) were reported several decades ago. Subse-
Finally, studies have examined genes that participate in the quently, investigation of autoantigens in hypertension was
activation of the inflammasome. The association between largely suspended. More recent studies have found prelim-
susceptibility to essential hypertension and the cold-in- inary evidence of autoantigenic reactivity to HSP70 and to
duced autoinflammatory syndrome 1 (CIAS1) gene was isoketal-modified proteins in subjects with essential hyper-
studied by Omi et al. (200) in 987 patients and 924 con- tension and will be discussed in the following sections.
trols. C1AS1 is a member of the NLRP3/ PYPAF subfamily
of the CATERPILLER protein family that regulates inflam-
1. HSP 70
masome-induced activation of NF␬B and caspase. Subjects
with 12–12 genotype of the C1AS1 42 bp-VNTR were
more frequently hypertensive than controls (P ⫽ 0.006). Plasma anti-HSP70 antibodies have been reported in pa-
This study suggests that genetic influences play a role in the tients with borderline hypertension (74) and hypertensive
activation of innate immune responses in patients with es- individuals working under stressful conditions (310). Pock-
sential hypertension. ely et al. (210) directly addressed the issue of antibodies
against HSPs and blood pressure in a study of 111 patients
with hypertension from the European Lacidipine Study on
Other elements of the innate immune response may play a
Atherosclerosis (ELSA) and 75 normotensive controls from
role in hypertension. A relative increase in neutrophil count,
a population screening program. They found that anti-
evaluated as the neutrophil-to-lymphocyte ratio, was re-
HSP65 and anti-HSP70 antibody titers were higher in hy-
cently found to be associated with the risk of hypertension
pertensive patients independently of age, smoking habits, or
(152).
blood lipids. Our group studied the proliferative response
to HSP70 in lymphocytes from 10 patients with essential
E. Agonistic Autoantibodies in Hypertension hypertension grade I or II and in 12 normotensive age- and
sex-matched controls. Peripheral blood lymphocytes were
cultured for 7 days with the HSP70 peptide used in toler-
Autoantibodies directed against G protein-coupled recep- ization and sensitization experiments described previously
tors (GPCR) have a functional response (stimulatory, inhib- (211). The lymphocytes of patients with essential hyperten-
itory, or synergistic) when they bind to their targets. Stim- sion responded with a high proliferation index, while the
ulatory (agonistic) autoantibodies recognize epitopes in the lymphocytes from controls were unresponsive (211). These
first or second extracellular loops of the receptor, and their studies, in a limited number of patients, raise the possibility
effects are associated with stabilization of the receptor-an- that a cellular immune response to HSP70 is activated in
tibody conformation after binding. As a result, they pro- essential hypertension. HSP70 mRNA was found increased in
mote sustained receptor activation resistant to the down- lymphocytes of hypertensive patients submitted to heat stress
regulation and to protective mechanisms associated with (145). In very recent studies, Srivastava et al. (253) studied the
the binding with the natural ligands. Agonistic antibodies blood of 132 patients with essential hypertension and 132
have been authoritatively reviewed (298, 313) and will not control individuals and found that hypertensive patients had a
be discussed here. In essential hypertension, anti-AT1r an- 6.4-fold higher HSP70 gene expression (P ⬍ 0.0001) as well as
tibodies are present in nearly 60% of the patients with increased HSP70 protein abundance (P ⬍ 0.0001). HSP70
refractory hypertension (331), but their clinical relevance mRNA correlated significantly with circulating levels of
remains unproven. Wei et al. (301) compared the effective- TNF␣, IL-6, and CRP.
ness of treatment with angiotensin receptor blockers
(candesartan) and angiotensin converting enzyme inhib- Finally, some studies have shown that polymorphisms in
itors (imidapril) in patients with moderate to severe es- the HSP70 gene family are associated with hypertension. Li
sential hypertension. The assumption was that the treat- et al. (149) studied 415 subjects (211 hypertensives) of the
ment with angiotensin receptor blockers would be more Uygur ethnic minority in China. This population is highly
effective if anti-AT1r antibodies had a relevant agonistic homogeneous and has unique diet and life styles. They eval-
activity. In a study of 512 subjects, half of which were uated the association between five polymorphisms in three
given candesartan and half imidapril, those patients who genes (HSPA1A, HSPA1B, and HSPA1L) of the HSP 70
had anti-AR1r antibodies had a more pronounced reduc- family and essential hypertension. In haplotype analyses
tion in blood pressure with candesartan than with imi- using the haplotype H1 as a reference, haplotype H4 had a
dapril. However, the study did not find correlation be- 40% reduced risk, while haplotypes H5 and H8 had a 5.00-
tween the titer of anti-AT1r antibodies and the efficacy of and 3.75-fold, respectively, increased risk for essential hy-
candesartan-based therapy. pertension. Nevertheless, as acknowledged by the authors

(149), the case-control characteristic of the study renders it The role of immune system in human hypertension is sup-
unsuitable for demonstrating a causality relationship. ported in a study by Herrera et al. (99) in which eight
patients with essential hypertension received MMF for co-
2. Isoketal-modified proteins existing rheumatoid arthritis or psoriasis without modifica-
tion of antihypertensive treatment or diet. Blood pressure
As discussed earlier, Harrison’s group (135) has presented fell during MMF treatment in association with reduction in
compelling evidence on the role of ␥-ketoaldehydes urinary RANTES and TNF-␣. When MMF was discontin-
(isoketal)-modified proteins in activating DCs for antigen ued, blood pressure returned to previously high levels, sug-
presentation in experimental models of hypertension. In gesting that amelioration of hypertension was the result of
addition to the experimental data, the authors studied 16 immune suppression.
normotensive subjects, 44 patients with well-controlled hy-
pertension, and 86 patients with resistant hypertension to
examine the participation of isoketals in the pathogenesis of XI. GUT MICROBIOTA AND
essential hypertension. They found that plasma F2-isopros- HYPERTENSION
tanes that are formed in concert with isoketals are increased
in patients with refractory hypertension, compared with The interaction between the gut microbiota and the im-
controlled hypertension and normotensive subjects (P ⬍ mune system in hypertension has been recently reviewed
0.05). In a second group of 12 patients with essential hy-
(123). Reduction in gut microbiota has been associated
pertension and 8 normotensive controls, the isoketal-pro-
with systemic inflammation and hypertension, and the ad-
tein adduct content in circulating mononuclear cells was
ministration of probiotics improves hypertension in ec-
analyzed by flow cytometry. Their data demonstrated that
lampsia (23). However, the mechanisms involved are
isoketal adducts in CD14⫹ cells and in CD83⫹ DCs from
hypertensive patients were severalfold higher than in nor- largely unknown. Specific immunomodulatory effects have
motensive controls. Highly significant correlations were been demonstrated in the Bacteroides fragilis where the
found between the systolic blood pressure and the percent- production of a polysaccharide is able to restore the Th1/
age of isoketal-positive CD14⫹ and CD83⫹ cells (135). Th2 balance in the germ-free mice and affect natural killer
More recently, it has been shown that the aortic content of cells. Lactobacilli produce peptides capable of inhibiting
isoketal-protein adducts is correlated with fibrosis and in- ACE1 (188), and Clostridium-related microorganisms can
flammation severity (311). induce Treg production in the colonic lamina propria and
IL-17 production in the small intestinal lamina propria
Investigations in humans supporting engagement of the in- (259). Olfactory receptors are expressed in the juxtaglo-
nate and adaptive immunity in the pathogenesis of essential merular apparatus in the kidney and respond to short-chain
hypertension are shown in FIGURE 8. fatty acids produced by gut microbiota that enter the circu-
lation by colonic absorption. The modulation of blood
pressure by propionate generated by gut microorganisms
G. Clinical Hypertension and Immune likely depends on the balance of two olfactory receptors:
Suppression OLfr 48 and Gpr41 (209).
Studies performed three decades ago reported that the ab- In the SHR there is a reduction in the richness of the gut
solute number of CD4⫹ T cells was reduced during treat-
microbiota and a high Firmicutes-to-Bacteroidetes ratio.
ment with ACE inhibitors and suggested that suppression of
Restoring this ratio with the administration of minocy-
the RAS had an effect on cellular immunity (245). These
cline improved hypertension. Differences in the constitu-
findings have not been investigated subsequently. More re-
tion of the gut microbiota have also been shown to exist
cently, the association of immune suppression with amelio-
in the Dahl SS and SR rats. Surprisingly, a single bolus of
ration of hypertension has been reported. Data from the
Multicenter AIDS Cohort study indicate that untreated fecal content of SS rats administered to SR rats increased
HIV-positive patients with chronically low numbers of the blood pressure of SR rats for the rest of their lives
CD4⫹ T cells have a lower prevalence of systolic hyperten- (178).
sion than treated HIV patients and uninfected control sub-
jects (236). Grome et al. (87) reported reduced brachial In a recent study, gut dysbiosis was found in a small group
artery flow-mediated vasodilatation associated with a of 7 hypertensive patients when compared with 10 normo-
higher percentage of activated (CD38⫹) CD8⫹T cells in 70 tensive controls (318), and a meta-analysis of 9 trials re-
HIV-infected adults. Higher ICAM-1 and VCAM-1 levels ported a minor reduction in blood pressure with the admin-
were associated with activated macrophages. These find- istration of probotics (131). Future studies will likely define
ings suggested a relationship between CD8⫹T cell activa- characteristics of the gut microbiota that, in conjunction
tion and impairment in arterial relaxation and between with other variables, may play a role in the modulation of
monocyte activation and immune cell vascular infiltration. blood pressure.

Adaptive ROS, uric acid, **HSP70,

Innate
*Isoketal modified proteins
Neoantigens Cellular stress
DAMPs
(*135, **211, **253)
APC (163)
PRR TLR2, TLR4
Antigen (*135)
T cell
Inflammasome
activation
B cell CD4+ CD8+

Monocyte Macrophage Neutrophil
(*135)
Th1, Th2, Treg
Th17
Antibodies (*135) Complement

DC NK
system
(**74,
IL-10, CTLA4
**210,
**310) (14, 115, (18, 45, 106,
IL-1β, IL-18 152, 270, 334)
118, 184)
INFLAMMATION
CNS/SNS
(*311) Vessels - Kidney (80, 97, 105, 248, 320)
Blood pressure
FIGURE 8. Innate and adaptive immune system in clinical hypertension. The innate and adaptive immunity
play a role in establishing inflammation in the kidney, arteries (perivascular), and central nervous system
(CNS)/sympathetic nervous system (SNS). Danger-associated molecular patterns (DAMPs) recognized by
pattern recognition receptors (PRR), specifically, Toll-like receptors (TLR), activate the inflammasome and drive
an innate immune response with the participation of monocytes (Mo), macrophages (M¢), dendritic cells (DC),
neutrophils (N), and natural killer cells (NK). Neoantigens generated (isoketal-modified proteins) and overex-
pressed immunodominant molecules (HSP70) are taken up by antigen presenting cells (APCs), presented for
recognition to the naive T lymphocytes in the context of the MHC to the specific T cell receptor. Stimulation of
antibody producing B cells and of helper (CD4⫹) and cytotoxic (CD8⫹) T cells takes place. CD4⫹ T cells
generate a proinflammatory Th1, Th2, and IL-17 cytokine responses and T regulatory cells (Tregs), required
for limiting inflammation. Numbers in parentheses indicate the references that support the finding in human
hypertension (*data for isoketal-modified proteins, **data for HSP70).
XII. CONCLUDING REMARKS We suggest that major issues that need to be addressed at
the present time include the following.
High blood pressure is a hemodynamic consequence of 1) Identification of genetic traits that have increased fre-
many factors, and there is now definitive evidence for a role quency in hypertensive patients and, additionally, are
of immunity in the pathogenesis of essential hypertension.
related to the immune response. The relevance of a given
As shown in FIGURE 9, the development and aggravation of
trait may be explored experimentally. This approach has
hypertension may be considered a stepwise process of en-
gagement of the immune system. This process originates already proved successful in several studies (226, 230).
from stimuli that activate innate immunity, first transiently 2) Identification of antigenic determinants in hypertension
and then permanently, in conjunction with an adaptive im- capable of activating T and B responses. These studies
mune response to neoantigens. The addition of chronic re- may lead to strategies directed to minimize their genera-
nal damage and arteriosclerosis increases the severity of tion or to suppress the immune responses driven by these
hypertension and its complications. antigens.

Blood pressure Activation of immune system Histology
CNS/SNS, Oxidative stress,

Prehypertension Uric acid, Renin-angiotensin, Normal
Autoimmune reactivity
DAMPs
Transient Expression of TLR Immune cell infiltration
hypertension Intermittent activation kidney, vessels, CNS
of innate immunity
Inflammation in perivascular
areas, renal tubulointerstitium,
Established Innate Adaptive brain circumventricular regions
hypertension immunity immunity in equilibrium with suppressive
(anti-inflammatory) reactivity
Severe Innate Adaptive Chronic renal damage

hypertension immunity immunity arteriosclerosis
FIGURE 9. Activation of the immune system and the natural history of essential hypertension. Prehyperten-
sion is associated with irregular generation of stimulatory signals associated with rise in blood pressure.
Transient episodes of hypertension are associated with episodic generation of danger-associated molecular
patterns (DAMPs) and expression of Toll-like receptors (TLRs) that activate intermittently the innate immune
system with episodic inflammatory infiltration in target organs. Established hypertension results from the
activation of both the innate and the adaptive immunity that support one another and drive a permanent renal
and vascular inflammation that is, nevertheless, in a state of unsteady equilibrium with the suppressive
(anti-inflammatory) responses. This balance is capable of maintaining a well-preserved renal function. The
development of chronic renal damage and arteriosclerosis, resulting from persistent and increasing inflam-
mation fueled by the unchecked generation of neoantigens, is manifested by hypertension of increased severity
and resistance to treatment.
3) Evaluation of mechanisms of engagement of innate im- postpones the need of an invasive procedure that is
munity in hypertension and determine if suppressing in- not devoid of complications (107).
flammasome activation results in prevention or correc-
tion of experimental hypertension. The availability of In moving forward, we need to be aware that although
compounds that inhibit the activation of the inflam- the mouse is conveniently used in experimental studies of
masome with relatively minor adverse effects (37) makes hypertension, the SHR and the Dahl SS rats are genetic
this line of investigation attractive. strains that resemble better human hypertension. Fur-
4) Investigation of the potential use of a short period of thermore, the use of intravenous infusions of angiotensin
immune suppression as valuable adjunct to antihy- II is an excellent way to dissect pathogenetic mechanisms,
pertensive medication in selected cases of severe re- but the doses frequently used likely result in circulating
sistant hypertension. To be sure, presently available levels of angiotensin that are several times higher than
antihypertensive drugs offer an effective and safe those present in physiological or physiopathological con-
treatment in the vast majority of hypertensive pa- ditions (162) and therefore of uncertain clinical rele-
tients without the complications of long-term im- vance.
munosuppression. Nevertheless, there are excep-
tional cases of severe hypertension that are resistant Much has been learned about the immune basis of hyper-
to treatment. In these patients, renal denervation tension in the last decade, and further research in the im-
has been used with variable success (107). We re- mune mechanisms participating in the pathogenesis of hy-
cently reported a patient with resistant hyperten- pertension may open new strategies in the treatment of the
sion, considered for renal denervation, in whom 2 disease.
mo of MMF treatment resulted in control of the
blood pressure with regular doses of antihyperten- ACKNOWLEDGMENTS
sive medication (217). While this anecdotal report
needs confirmation, it is not unreasonable to evalu- Address for reprint requests and other correspondence: B.
ate if a few weeks of immunosuppression avoids or Rodriguez-Iturbe, Hospital Universitario de Maracaibo,

Servicio de Nefrología, Ave. Goajira, Maracaibo, Venezu- masome activation by regulating NLRP3 expression. J Immunol 183: 787–791, 2009.
doi:10.4049/jimmunol.0901363.
ela (e-mail: brodrigueziturbe@gmail.com).
12. Bautista LE, Atwood JE, O’Malley PG, Taylor AJ. Association between C-reactive
GRANTS protein and hypertension in healthy middle-aged men and women. Coron Artery Dis
15: 331–336, 2004. doi:10.1097/00019501-200409000-00006.
The work in the authors’ laboratories is funded by grants 13. Bautista LE, López-Jaramillo P, Vera LM, Casas JP, Otero AP, Guaracao AI. Is C-re-
active protein an independent risk factor for essential hypertension? J Hypertens 19:
from FONACYT, Venezuela (FC-2005000283, to B. Ro- 857– 861, 2001. doi:10.1097/00004872-200105000-00004.
driguez-Iturbe) and Asociación de Amigos del Riñón (to B.
Rodriguez-Iturbe) and by National Heart, Lung, and Blood 14. Bautista LE, Vera LM, Arenas IA, Gamarra G. Independent association between in-
flammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential
Institute Grant HL-68607 (to R. J. Johnson). hypertension. J Hum Hypertens 19: 149 –154, 2005. doi:10.1038/sj.jhh.1001785.
15. Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat
DISCLOSURES produces systemic hypertension and glomerular damage. J Clin Invest 90: 278 –281,
1992. doi:10.1172/JCI115849.
R. J. Johnson is on the Scientific Board of Amway and 16. Ben-Ishay D, Saliternik R, Welner A. Separation of two strains of rats with inbred
dissimilar sensitivity to Doca-salt hypertension. Experientia 28: 1321–1322, 1972.
XORT Therapeutics and has patent and patent applications doi:10.1007/BF01965321.
related to lowering uric acid or blocking fructose metabo-
17. Binger KJ, Gebhardt M, Heinig M, Rintisch C, Schroeder A, Neuhofer W, Hilgers K,
lism in the treatment of hypertension and metabolic disor- Manzel A, Schwartz C, Kleinewietfeld M, Voelkl J, Schatz V, Linker RA, Lang F,
ders. H. Pons and B. Rodriguez-Iturbe have no conflicts of Voehringer D, Wright MD, Hubner N, Dechend R, Jantsch J, Titze J, Müller DN. High
interest, financial or otherwise. salt reduces the activation of IL-4- and IL-13-stimulated macrophages. J Clin Invest
125: 4223– 4238, 2015. doi:10.1172/JCI80919.
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Physiol Rev 97: 1127–1164, 2017

Published May 31, 2017; doi:10.1152/physrev.00031.2016

ROL DEL SISTEMA INMUNE EN LA

L Rev 97: 1127–1164, 2017. Publicado el 31 de mayo, 2017; doi:10.1152/physrev.00031.2016. —

I. INTRODUCTION 1127 proved therapeutic options, is uncontrolled in 8 –12% of

0031-9333/17 Copyright © 2017 the American Physiological Society 1127

Strain Experimental Strategy/Treatment Untreated Treated

Spontaneously hypertensive rat (SHR) Cyclophosphamide (132) 172 153

1128 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1129

1130 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

He described an early hypertension (30 – 40 days postoper- 4. Cellophane-wrapped kidneys

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1131

1132 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1133

1134 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1135

1136 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Table 2. Effects of suppressing individual cytokines in experimental models of hypertension

the variability in the amelioration of hypertension attrib- B. TNF-␣

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1137

1138 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

J. IL-17 Several investigations have studied the role played by the

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1139

FIGURE 1. Participation of the NLRP3 inflammasome in the pathogenesis of experimental hypertension. 1)

1140 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

NLRP3 ASC Procaspase

0.0 0.0 0.0

Caspase IL-1β IL-18

0.4 0.4 1.0

0.2 0.2 0.5

0.0 0.0 0.0

WKY SHR WKY SHR WKY SHR

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1141

SHR Anti-TLR4 Hypertension ameliorated (MAP: not treated ⫽ 160 mmHg; 20

1142 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Arteries, Kidney Spleen

FIGURE 3. Adaptive immunity in experimental hypertension. Investigations demonstrating involvement of

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1143

WKY (4wks old) SHR (4 wks old)

WKY (40 wks old) SHR (40 wks old)

HSP72 HSP70 SHR

0.0 0.0 0.0 0.0

1144 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1145

A PAS CD68 ANGII B

90 110 130 150

1146 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1147

Systemic inflammation (309)

PVR Central nervous system

Kidney Dendritic cells

Immune cell Co-stimulation markers

CD4+, CD8+, CD3+ and

1148 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

The role of the SNS as a mediator of the renal inflamma-

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1149

Mirhafez et al. (184) examined the blood levels of 12 cyto-

1150 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Physiol Rev • VOL 97 • JULY 2017 • www.prv.org 1151

1152 Physiol Rev • VOL 97 • JULY 2017 • www.prv.org

Adaptive ROS, uric acid, **HSP70,

B cell CD4+ CD8+