Am J Physiol Renal Physiol 304: F1231–F1242, 2013.

First published March 20, 2013; doi:10.1152/ajprenal.00557.2012. Review

Tumor necrosis factor-␣: regulation of renal function and blood pressure

Vanesa D. Ramseyer1,2 and Jeffrey L. Garvin1,2,3
1
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
2
Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan; and 3Department of Physiology
and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio
Submitted 27 September 2012; accepted in final form 15 March 2013

Ramseyer VD, Garvin JL. Tumor necrosis factor-␣: regulation of renal

function and blood pressure. Am J Physiol Renal Physiol 304: F1231–F1242, 2013.
First published March 20, 2013; doi:10.1152/ajprenal.00557.2012.—Tumor necro-
sis factor-␣ (TNF-␣) is a pleiotropic cytokine that becomes elevated in chronic
inflammatory states such as hypertension and diabetes and has been found to
mediate both increases and decreases in blood pressure. High levels of TNF-␣
decrease blood pressure, whereas moderate increases in TNF-␣ have been associ-
ated with increased NaCl retention and hypertension. The explanation for these
disparate effects is not clear but could simply be due to different concentrations of
TNF-␣ within the kidney, the physiological status of the subject, or the type of
stimulus initiating the inflammatory response. TNF-␣ alters renal hemodynamics
and nephron transport, affecting both activity and expression of transporters. It also
mediates organ damage by stimulating immune cell infiltration and cell death. Here
we will summarize the available findings and attempt to provide plausible expla-
nations for such discrepancies.
TNF-␣; hypertension; natriuresis; TNF receptor; septic shock; transport; renal
hemodynamics; blood pressure

Tumor Necrosis Factor-␣ in the Kidney: Synthesis
and Secretion
TNF-␣ IS A PROINFLAMMATORY cytokine that was originally
described as antitumorigenic (19, 60) and produced by immune
cells like macrophages and lymphocytes (15, 105, 142); how-
ever, further studies revealed it is also produced by endothelial
and epithelial cells (14, 43, 61, 66, 71, 98, 99, 101, 141, 160).
TNF-␣ is expressed as a 26-kDa plasma membrane protein that
is secreted into the extracellular space by the metalloproteinase
TNF-␣-converting enzyme (TACE, also called a disintegrin
and metalloproteinase 17 or ADAM 17; Refs. 16, 76, 89). In
solution, this 17-kDa protein forms homotrimers and activates
two distinct receptors (151). Transmembrane TNF-␣ also
forms trimers (136) and can activate TNF receptors. Moreover,
the intracellular domain of transmembrane TNF is palmitoy-
lated (148) and can be phosphorylated (111), providing an
additional step for regulation of TNF-␣ release.
Infiltrating inflammatory cells (142), podocytes (119), mes-
angial cells (6, 13, 14, 74), and epithelial cells from proximal
tubules (101, 113, 163, 164), thick ascending limbs (3, 35, 90,
156) and collecting ducts (140) are sources of TNF-␣ in the
kidney. TNF-␣ increases in response to endotoxemia (26),
lipopolysaccharide (LPS; Refs. 34, 40, 74, 90), angiotensin II
(ANG II; Ref. 35), calcium-sensing receptor (CaSR) activation
(3, 156), hypertension (32, 79), renal failure (115), glomeru-
lonephritis (153), diabetic nephropathy (42, 100), and intersti-
tial tubular nephritis (50, 94).
Address for reprint requests and other correspondence: V. D. Ramseyer,
Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West
Grand Boulevard, Detroit, MI 48202-2689 (e-mail: vramsey1@hfhs.org).
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TNF-␣ production is augmented in proximal tubule cells in
response to IL-1␣ but not IL-2 or IFN␥ (161). This increase is
inhibited by cycloheximide, suggesting that it is not due to
increased TNF shedding from the membrane but rather en-
hanced protein synthesis.
In the thick ascending limb, CaSR activation stimulates Gi
and Gq protein (3); this activates phosphatidylinositol-specific
phospholipase C, which in turn produces inositol triphosphate
and diacylglycerol. Inositol triphosphate increases intracellular
Ca, which forms a complex with calmodulin whereas diacyl-
glycerol activates protein kinase C (PKC). These two conver-
gent cascades lead to activation of calcineurin. Activated
calcineurin dephosphorylates nuclear factor of activated T cells
(NFAT), allowing translocation of this transcription factor to
the nucleus and transcription of TNF-␣ (1, 3, 156). In partic-
ular, NFAT5 (also called Ton/EBP for tonicity element binding
protein) has been shown to partially mediate the CaSR-induced
increase in TNF-␣ expression (53) and is itself activated by
changes in osmolality in renal cells (95); however, it is not
known whether changes in osmolality induce TNF-␣ release by
thick ascending limbs nor whether this TNF-␣ release is
mediated via NFAT5.
TNF-␣ levels have been shown to increase in response to
ANG II in thick ascending limbs (35) and podocytes (119). In
podocytes, activation of both AT1 and AT2 receptors was
responsible for this effect, with AT1 mediating the earlier
phase and AT2 the later phase. ANG II activates PKC in the
thick ascending limb (57, 128) and thus may increase NFAT
translocation to the nucleus along with TNF-␣ gene transcrip-
tion; however, it is still unclear whether PKC and NFAT
mediate ANG II-induced increases in TNF-␣ expression in the
thick ascending limb. In addition, TNF-␣ production is known
F1231
Review
F1232 TNF AND RENAL FUNCTION
to increase in response to LPS in thick ascending limbs and
podocytes, particularly during endotoxemia.
Finally, TNF-␣ production in the kidney can be increased by
infiltrating immune cells, especially macrophages (105, 142,
169). Increased innate immune activation, neutrophil and mac-
rophage infiltration, and enhanced TNF-␣ production are ob-
served in infections (83), cisplatin nephropathy (73, 114),
diabetic nephropaty (38), antiglomerular basement membrane
nephropathy (142), obstructive nephropathy (134), etc. In such
situations stimuli for TNF-␣ production include activation of
Toll-like receptor 4 in response to LPS (85), oxidative stress
(30), antibody deposition, and complement activation (142,
159). In addition, dendritic cell, macrophage, and lymphocyte
recruitment to the kidney is observed in lupus erythematosus
and hypertension (27, 51, 96). The stimuli for their migration
to the kidney and TNF-␣ production are likely increased
reactive oxygen species and enhanced expression of endothe-
lial adhesion molecules and chemokines by the kidney in
response to elevations in renal-derived TNF-␣. Inhibition of
AT1 receptors (7, 121) as well as reactive oxygen scavenging
(30) reduces renal-derived TNF-␣, proinflammatory cytokine
production, and immune cell infiltration and activation. Simi-
larly, ANG II infusion increases leukocyte infiltration and
production of inflammatory cytokines, all of which are pre-
vented by blockade of TNF-␣ with etanercept (33, 96). These
data indicate that endotoxins, ANG II, and reactive oxygen
species stimulate TNF-␣ expression by the kidney; this in turn
induces inflammatory cell recruitment and activation, which
further increase TNF-␣ levels.
TNF-␣ Receptors
The actions of TNF-␣ are mediated by two distinct recep-
tors: type 1 (TNFR1 or p55) and type 2 (TNFR2 or p75).
Kinetically, TNF-␣ binding to TNFR1 shows slow dissocia-
tion, whereas it is 20 –30 times faster with TNFR2 (48).
Therefore, some have proposed that TNFR2 serves as a “local
reservoir” of TNF-␣, both providing readily available TNF-␣
for TNFR1 activation and operating as a “ligand passing”
receptor in which TNFR2 captures TNF-␣ and passes it on to
TNFR1. In addition, it has been shown that TNFR1 activation
requires expression of TNFR2, which can form heterocom-
plexes with TNFR1 (28, 87, 107). Although the effects of
soluble TNF-␣ may be mediated by either receptor, most of the
actions of membrane-bound TNF-␣ are mediated by TNFR2
(47). TNFRs form homotrimers in the plasma membrane via
their preligand assembly domain (22). TNFRs do not have an
intrinsic catalytic property; rather, ligand binding causes a
conformational change in the preassembled receptor that leads
to recruitment of signaling proteins.
In healthy animals, TNFR1 and 2 have been found in the
cortex in proximal tubules and collecting ducts as well as
endothelial cells of the glomeruli and renal vasculature (8, 20).
TNFR1 has also been found in vascular smooth muscle cells of
the renal vasculature (20). However, TNFR expression varies
in different diseases. In glomerulonephritic kidneys, TNFR2
expression was high in glomeruli and postcapillary venules of
the cortex, whereas in obstructive nephropathy (which primar-
ily affects tubules) TNFR2 staining was restricted to tubular
epithelial cells (153). ANG II also increases TNFR1 and 2
expression in podocytes (119). Thus one would expect that if
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ANG II is elevated (under conditions like low-salt diet, renal
vascular hypertension, etc.), then receptor expression would be
elevated as well. Such data suggest that the cellular pattern of
TNFR expression in the kidney could affect its response to
TNF-␣ depending on its initial physiological/pathophysiolog-
ical state.
TNF-␣ and Blood Pressure
The role of TNF-␣ in blood pressure regulation has been
studied in several different models, with sometimes conflicting
results. There are a number of reports showing that TNF-␣
either mediates or supports increases in blood pressure. In
ANG II-infused hypertensive rats fed high-salt diet, etanercept
delayed progression of hypertension. Protection appeared to be
due to reduced renal damage, since proteinuria and monocyte/
macrophage infiltration were diminished (33). In addition,
infusion of ANG II for 2 wk failed to increase blood pressure
in TNF-␣ knockout (KO) mice, but this was restored by replace-
ment therapy with recombinant TNF-␣ (0.3 ␮g·kg⫺1·day⫺1; Ref.
131). In addition, Guzik et al. (51) showed that TNF-␣ pro-
duction by T lymphocytes from ANG II-hypertensive mice was
higher than in control mice and that etanercept infusion blunted
ANG II-induced increases in blood pressure. These data seem
to indicate that TNF-␣ mediates ANG II-dependent increases
in blood pressure. Similarly, in a mouse model of lupus
erythematosus etanercept infusion for 4 wk reduced blood
pressure, albuminuria, glomerulosclerosis, and NF-␬B activity,
suggesting that TNF-␣ causes inflammation and mediates the
increase in blood pressure (152).
Metabolic syndrome is characterized by the simultaneous
presence of obesity, dyslipidemia, insulin resistance, and hy-
pertension. It has been shown that elevated TNF-␣ levels are
associated with the development of hypertension (63, 170).
Etanercept treatment for 6 wk prevented the increase in blood
pressure observed in insulin-resistant fructose-fed rats without
affecting insulin sensitivity (147). TNF-␣ neutralization also
restored maximum acetylcholine-induced relaxation in mesen-
teric arteries and restored nitric oxide synthase 3 (NOS3)
expression (147).
TNF-␣ also appears to play a role in blood pressure regula-
tion during pregnancy. In preeclampsia, plasma TNF-␣ is
doubled (10, 25, 122), and infusing TNF-␣ for 5 days (⬍0.5
␮g·kg⫺1·day⫺1) increases blood pressure in pregnant rats but
not in virgin rats (80, 81). Blockade of TNF-␣ with etanercept
reduced blood pressure. In addition, healthy endothelial cells
incubated with serum from preeclamptic rats exhibited in-
creased endothelin-1 release and this was prevented by etan-
ercept (79). Similarly, infusion of a neutralizing anti-TNF
antibody reduced blood pressure, albuminuria, and renal dam-
age in a model of preeclampsia achieved by adoptive transfer
of serum from preeclamptic women to pregnant mice (62).
Finally, TNF-␣ is increased is chronic kidney disease, which
is characterized by progressive loss of renal function, renal
injury, and hypertension (130, 139, 162). This disease can be
mimicked by 5/6 nephrectomy, which also increases TNF-␣
release. In rats with renal failure, neutralizing TNF-␣ with
soluble TNFR1 prevented the increase in blood pressure,
reduced fibrosis, decreased macrophage infiltration and albu-
minuria, and restored the ratio of L-arginine to asymmetric
dimethylarginine (139). It also restored expression of NOS3,

TNF AND RENAL FUNCTION
endothelin-1, transforming growth factor-␤ macrophage che-
moattractant protein, intercellular adhesion molecules, and
vascular cell adhesion molecules (139).
However, there are also a number of reports indicating that
TNF-␣ either plays no role or tends to reduce blood pressure.
For example, in DOCA-salt hypertensive rats etanercept did
not reduce blood pressure (32). Although it remains unclear
why TNF-␣ blockade failed to afford protection in these rats,
it could be due to the high systolic blood pressure, or it could
simply be that TNF-␣ does not participate in this model of
hypertension. Supporting this notion is the fact that the DOCA-
salt model of hypertension is based on elevated mineralocor-
ticoid levels, and the increase in blood pressure can be pre-
vented with mineralocorticoid receptor antagonists (44, 149).
In addition, Muller et al. (96) showed that in a double-
transgenic rat model of ANG II-dependent hypertension, in
which human angiotensinogen and renin are expressed, etan-
ercept did not alter blood pressure even though it reduced
albuminuria and infiltration by inflammatory cells. The dispar-
ity with the previous report by Elmarakby et al. (33) in which
TNF-␣ blockade delayed the increase in blood pressure in
ANG II-induced hypertension could be explained by the fol-
lowing facts: 1) Muller et al. started anti-TNF treatment after
rats were hypertensive whereas Elmarakby et al. started ANG
II and etanercept at the same time; 2) the blood pressure in the
double-transgenic rats was much higher than in those infused
with ANG II; 3) Muller et al. only measured blood pressure at
day 20 whereas Elmarakby et al. found that the blood pressure-
lowering effect of etanercept took place from days 6 to 12 after
the start of the anti-TNF treatment; and 4) Muller et al. used
regular salt diet while Elmarakby et al. fed the rats high-salt
diet.
Using a different anti-TNF treatment, Ferreri et al. (36)
showed that in ANG II-induced hypertension a neutralizing
anti-TNF antibody induced an acute increase in blood pressure
after 30 min of infusion. The explanation for this discrepancy
is unclear but is likely the duration of the study. In reports
where TNF-␣ was found to mediate increases in blood
pressure, animals were studied for weeks rather than hours
or days. These investigators later showed that infusion of
1.6 ␮g·kg⫺1·min⫺1 ANG II raised blood pressure higher in
TNFR1 KO mice than in wild-type (WT) at 2, 4, and 5 days of
ANG II infusion. Proteinuria, water intake, glomerular filtra-
tion rate (GFR), and urinary output were also increased
whereas Na excretion was reduced, suggesting increased renal
Na reabsorption. These results are in stark contrast to those
shown in TNF-␣ KO mice (131) where the increase in blood
pressure induced by infusion of 1 ␮g·kg⫺1·min⫺1 ANG II was
blunted compared with WT mice and to those shown by Guzik
et al. (51) where etanercept reduced the increase in blood
pressure induced by infusion of ANG II at a rate of 490
ng·kg⫺1·min⫺. While the explanation is not clear, it could be
due to the different doses of ANG II used (and hence possibly
different mechanisms leading to hypertension), due to the
background of the mice (C57Bc/6J vs. B6129SF2/J), or be-
cause infusion of ANG II in TNFR1 KO mice increases both
TNF-␣ and TNFR2 (24). This later point raises the possibility
that the observed phenotype is the result of hyperactive TNFR2
as opposed to a lack of TNFR1 and TNFR2 has been shown to
mediate renal macrophage infiltration, glomerulosclerosis, and
interstitial fibrosis in ANG II-induced hypertension (129).
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Review
F1233
In contrast to the link between TNF-␣ and hypertension,
TNF-␣ also appears to play a role in the hypotension associated
with septic shock (145). This is a complex pathological con-
dition that results from an exaggerated and deregulated host
response to infection with extreme increases in TNF-␣ levels.
Activation of the innate immune response with increased
neutrophil and macrophage tissue infiltration is observed.
However, attempts to reduce the immune response by blocking
the action of TNF or inhibiting downstream mediators have
provided conflicting results. Indeed, in animals pretreatment
with TNF-␣ blockers like neutralizing antibodies (37, 146) or
soluble receptor fusion constructs (150) before the onset of
sepsis has shown a positive outcome with a lower mortality
rate; however, in humans numerous trials have failed to dem-
onstrate a beneficial effect of anti-TNF therapy in septic
patients (4, 41, 112). Failure of this approach is partly attrib-
uted to the need of a competent immune system to withstand
the systemic infection and partly to the fact that in humans
treatment is started after sepsis has been initiated. TNF-␣
decreases blood pressure in septic shock by numerous mech-
anisms, including reductions in cardiac contractility (77, 165),
increased endothelial permeability (5, 97), exaggerated NO
production (72), resistance to catecholamines (17, 158), in-
creased sodium excretion (126), and decreases in vasopressin
receptors and aquaporin 2 (58).
Why TNF-␣ is implicated as a causative agent of both
increases and decreases in blood pressure is not clear. When
considered in toto, most evidence seems to support a role for
chronic moderately elevated concentrations of TNF-␣ in hy-
pertension, as the opposing reports have alternative explana-
tions. This view is also supported by the fact that nearly all
studies show that neutralizing TNF-␣ protects against renal
damage, which in itself is a cause of hypertension. In contrast,
higher concentrations of TNF-␣ are associated with decreases
in blood pressure and more severe inflammation. In these cases
the decrease in blood pressure is likely dependent on both renal
and nonrenal systemic actions of TNF-␣ (Fig. 1).
180
re
↑ macrophage infiltration
blood pressur
↑ neutrophile infiltration
↓ ↓ GFR
↓ ↓ RBF
p
120 ↓ Renal NaCl reabsorption
mmHg))
↑ macrophage infiltration ↓ proteinuria
↑ lymphocyte activation
↓ NOS3 and NO
Renal failure
(m
ystolic b
↑ Renal NaCl reabsorption
60
↑ renal damage
↑ proteinuria
Sy
1 2 5 10
TNF in plasma (fold increase from normal levels)
Fig. 1. Diagram representing the effects of increasing levels of TNF-␣ in renal
function and the hypothetical effect on blood pressure. Increases of 1- to 2-fold in
TNF-␣ are present in hypertension whereas increases of TNF-␣ ⬎5 times are
observed in septic shock. Dashed line represents a theoretical relationship between
TNF-␣ levels and blood pressure. NO, nitric oxide; NOS3, nitric oxide synthase
type 3; GFR, glomerular filtration rate; RBF, renal blood flow.
Review
F1234 TNF AND RENAL FUNCTION
Renal Hemodynamics
At high doses (ⱖ0.6 mg/kg), infusion of TNF-␣ in healthy
rats lowers blood pressure. This is accompanied by lower GFR
and renal blood flow (RBF); however, renal vascular resistance
(RVR) increases (20, 127). The decreases in GFR and RBF can
be explained by the drop in blood pressure, which was shown
to be due to an increase in nitric oxide synthase type 2 (NOS2;
Refs. 72, 91, 117), but this cannot be the entire explanation as
RVR increases. Elevated RVR has been related to increases in
superoxide production (127), and it may be due to TNF-␣
acting differently on renal vessels than those of the general
circulation or on nephron segments that alter RVR such as the
macula densa or connecting tubule. Increased RVR and re-
duced RBF and GFR were observed in both WT and TNFR2
KO mice but absent in TNFR1 KO, suggesting that the re-
sponse was due to activation of TNFR1. Activation of TNFR2
(TNF-␣ treatment in TNFR1 KO mice) dilated blood vessels.
Thus the effect of TNF-␣ on renal hemodynamics in healthy
animals is mediated primarily by TNFR1 (20).
Renin-Angiotensin System
TNF-␣ decreases renin promoter activity and expression in
primary cultures of juxtaglomerular (JG) cells and in As4.1
cells (a cell line that constitutively releases renin). In As4.1
cells, TNF-␣ (0.1 to 100 ng/ml) reduces renin release after 30
h of treatment. Moreover, TNF-␣ KO mice show a threefold
increase in renal renin mRNA content but not changes in
plasma renin activity. These data suggest that TNF-␣ nega-
tively regulates renin expression via a reduction in mRNA
levels due to declining transcription (144).
Todorov et al. (144) showed that TNF-␣ actions on renin
expression were dependent on NF-␬B binding to a cAMP-
responsive element (CRE) located on the renin promoter.
Binding of the proteins NF-␬B-p50, p-65, p-52, and c-Rel to
CRE lowered transcription. The transcriptional coactivator
CBP, the protein that binds the transcription factor CRE
binding protein (CREB), interacts with NF-␬B and CREB/ATF
transcription factors to initiate transcription; however, silenc-
ing CBP did not affect TNF-induced decreases in renin mRNA
or promoter activity. Therefore, the authors concluded the
effect most likely is not due to NF-␬B competing with CREB/
ATF for CBP but rather that NF-␬B represses transcription
after binding to CRE. This conclusion is supported by the
ability of c-Rel to act as a transcriptional repressor (92).
Although TNF-␣ decreases renin content, it does not reduce renin
release by primary cultures of JG cells, and plasma renin activity
is not significantly increased in TNF-␣ KO mice. Thus the acute
effects of TNF-␣ on blood pressure are not likely due to changes
in plasma renin activity (144).
Similar to its effect on renin levels, TNF-␣ was shown to
reduce angiotensinogen levels in human kidney 2 (HK-2) cells,
a renal proximal tubular cell line (123). Since intrarenal ang-
iotensinogen levels correlate with blood pressure and are in-
dependent of plasma levels (45), in theory TNF-␣ could lower
blood pressure by reducing angiotensinogen expression. How-
ever, to the best of our knowledge neither intrarenal nor
intratubular levels of angiotensinogen have been measured in
TNF-␣ KO mice nor has the receptor involved been identified.
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Na, Water, Urea, and Glucose Transport
In spite of reductions in GFR and RBF in models of sepsis
and during acute TNF-␣ infusion, urinary Na excretion in-
creases. This indicates that TNF-␣ directly affects Na absorp-
tion along the nephron transport pathway independently of
changes in renal hemodynamics. The effects of TNF-␣ have
been studied in proximal tubular cells, thick ascending limbs,
distal tubular cells, and collecting ducts.
In LLCPk1 cells, a model of proximal tubule cells, TNF-␣
increases paracellular permeability, thereby activating extra-
cellular signal-regulated kinases (ERK), which results in phos-
phorylation of the guanidine exchange factor GEF-H1. Phos-
phorylated GEF-H1 enhances RhoA GTPase, which binds and
activates Rho kinase and increases myosin light chain phos-
phorylation, due in part to Rho kinase-induced inhibition of
myosin light chain phosphatase and in part to direct activation
of myosin light chain kinase. The increase in paracellular
permeability is preceded by increased cofilin phosphorylation
and formation of actin stress fibers (69, 70). Whether the
increase in paracellular permeability increases or decreases net
Na and fluid absorption is unclear from these reports, as they
were not measured directly and arguments can be made either
way. However, given that TNF-␣ reduces expression of renal
Na-K-ATPase (126), which ultimately drives all Na absorption in
the proximal nephron, it is likely that the combined actions of
TNF-␣ on proximal nephron transport are inhibitory (Fig. 2A).
TNF-␣ also enhances NO formation in proximal tubular
cells due to increased inducible NO synthase (iNOS or NOS2;
Refs. 68, 91). Although one report indicated that NO stimu-
lated proximal tubule transport (157), most have shown that it
inhibits Na and fluid absorption in this segment (31, 118). Thus
NO-induced inhibition of proximal reabsorption could account
for at least part of the increase in urinary Na excretion seen
when TNF-␣ is infused. Whether the TNF-␣-induced increase
in paracellular permeability in proximal tubules depends on
NO remains unclear.
In the thick ascending limb, ANG II and CaSR increase
TNF-␣ release (3, 35, 156). In this nephron segment, both
endogenous and exogenous TNF-␣ reduce NaCl transport via
activation of cyclooxygenase (COX2)-induced increases in
prostaglandin E (PGE) and inhibition of the Na-K-2Cl cotrans-
porter (NKCC2; Refs. 2, 3, 12, 34). Increased TNF-␣ sup-
presses Rb uptake, a measure of thick ascending limb ion
transport. In addition, activation of CaSR, which increases
TNF-␣ release, has also been shown to increase COX2 expres-
sion and reduce ouabain-sensitive oxygen consumption in the
thick ascending limb (2, 155), which may explain how CaSR
activation leads to natriuresis.
About 80% of transcellular Na reabsorption in the thick
ascending limb occurs through NKCC2. There are three iso-
forms of this transporter: A, B, and F. A is found throughout
the thick ascending limb, B mainly in the cortex, and F
primarily in the medulla. The level of expression in the kidney
is 10B:20A:70F, and the order of ion affinity is NKCC2B ⬎
NKCC2A ⬎ NKCC2F (21). In TNF-␣ KO mice, expression of
the A isoform was upregulated and this was reversed by
infusion of TNF-␣ (0.01 mg·kg⫺1·day⫺1), whereas the other
isoforms did not change; in addition, bumetanide-sensitive O2
consumption (an indicator of NKCC2 activity) was increased
in TNF-␣ KO mice and was also restored by TNF-␣ infusion
 Review
TNF AND RENAL FUNCTION F1235

Fig. 2. Cartoon showing the effects of TNF-␣ on ion transport in

vitro in epithelial cells of the kidney. Effects of TNF-␣ in proximal
tubular cells (A), in thick ascending limb cells (B), and in collecting
duct cells (C). Red boxes and arrows represent pathways activated
by TNF-␣ that are likely to increase Na reabsorption. Green boxes
and arrows represent pathways activated by TNF-␣ that are likely
to inhibit Na reabsorption. TNFR, TNF-␣ receptor; NHE3, Na/H
exchanger type 3; NOS2, nitric oxide synthase type 2; ERK,
extracellular signal-regulated kinases; Pi, phosphate; pGEF-H1,
phosphorylated guanine nucleotide exchange factor-H1; ROCK,
Rho-dependent kinase; MLCK, myosin light chain kinase; pMLC,
phosphorylated myosin light chain; SF, actin stress fibers; NKCC2,
Na-K-2Cl cotransporter; COX2, cyclooxygenase type 2; PGE2,
prostaglandin type 2; CaSR, calcium-sensitive receptor; ANG II,
angiotensin II; ENaC, epithelial Na channel; PKA, cAMP-depen-
dent protein kinase; PI3K, phosphatidylinositol 3 kinase; SMase,
sphingomyelinase; PKC, protein kinase C.

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Review
F1236 TNF AND RENAL FUNCTION
(12). In addition to reducing NKCC2, TNF-␣ reduces expres-
sion of thick ascending limb K channels (126), which would
also be expected to reduce Na absorption. Finally, TNF-␣
reduces NOS3 expression and NO production in this nephron
segment (116). NO produced in response to arginine (103, 110)
endothelin-1 (109, 56) and clonidine (108) reduces NaCl re-
absorption mainly by decreasing NKCC2 activity by the thick
ascending limb. These data suggest that TNF-␣ affects Na
transport regulation by the thick ascending limb by reducing
basal Na reabsorption while blunting the ability of other
natriuretic autacoids and hormones to further decrease trans-
port. Given that thick ascending limbs absorb 30% of the
filtered Na load, it is likely that direct actions of TNF-␣ in this
segment contribute to elevated Na excretion (Fig. 2B).
In Madin-Darby canine kidney cells, a canine model of
distal tubular cells, TNF-␣ increases paracellular permeability
by activating RhoA GTPase, Rho kinase, and myosin light
chain kinase, similar to LLCPk1 cells (69, 70). The net effect
of this activity on transport is unknown.
In mpkCCDcL4 cells, a murine collecting duct cell line, 10
ng/ml TNF-␣ increased protein kinase A (PKA) activity inde-
pendently of cAMP. LPS and TNF-␣ both increased transep-
ithelial Na transport, measured as an increase in amiloride-
sensitive short-circuit current, and this effect depended on
PKA activation (154). In contrast, in Xenopus distal nephron
cells (A6), 100 ng/ml TNF-␣ inhibited endothelial Na channel
(ENaC) activity by reducing the channel open probability;
however, this effect was only seen when phosphatidylinositol
3-kinase (PI3K) was inhibited. TNF-␣ inhibited ENaC via a
mechanism that involved activation of sphingomyelinase and
increased ceramide and activation of PKC, which in turn
induced externalization of phosphatidylserine. The presence of
phosphatidylserine in the cytosolic leaflet of the apical mem-
brane is sufficient to maintain ENaC activity; thus disappear-
ance of this phospholipid from the inner leaflet was likely the
cause of reduced ENaC activity (11). The role of PI3K in
preventing this effect was attributed to its ability to inhibit
sphingomyelinase activity (18). These disparate findings could
be explained by differences in the concentration of TNF-␣
tested, the experimental conditions, or the origin of the respec-
tive cells. For example, the A6 cells were grown with 1 ␮g
aldosterone whereas the mpkCCD cells were not, and aldoste-
rone activates PI3K (55). Whether or not other pertinent
hormones are also present in the collecting duct and ultimately
determine whether TNF-␣ increases or decreases ENaC activ-
ity could be the key to understanding its opposing effects on
tubular transport and blood pressure. When infused in vivo,
TNF-␣ reduces expression of all three subunits of ENaC (126);
thus its actions on the cortical collecting duct likely also
contribute to the natriuresis caused by systemic infusion (Fig.
2C). Finally, TNF-␣ increases nitrate/nitrite formation in inner
medullary collecting ducts, suggesting elevated NO production
that was supported by increased iNOS (68, 91) and NO has
been reported to inhibit Na reabsorption by this segment (132).
TNF-␣ KO mice showed increased ambient urinary osmo-
lality compared with WT, but water deprivation for 24 h
increased urine osmolality to the same extent in both strains
(12). LPS, which potently induces TNF-␣ release, decreases
arginine-vasopressin type 2 receptor levels and aquaporin 2
expression in the renal inner medulla (49). In support of this, in
a model of sepsis plasma arginine vasopressin did not change
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but V2 receptor and aquaporin 2 expression were decreased,
whereas a siRNA against the TNFR p50 subunit attenuated the
decrease in these proteins (58). Thus TNF-␣ may reduce
vasopressin-dependent water retention due to both inhibition of
water transport and reductions in the osmotic gradient developed
by the thick ascending limb, which drives water absorption.
Maintenance of urinary osmolality depends not only on
water and Na but also in large measure on urea. Blous infusion
of TNF-␣ at a dose of 1 mg/kg decreased fractional urea
excretion, inner medulla urea concentration and osmolality,
tubular urea reabsorption, and urinary urea, whereas it
increased plasma osmolality and urea. Such findings were
attributed to reduced urea transporters UTA1, UTA2, UT-A3,
UT-A4, and UT-B (124).
In addition to affecting Na and fluid absorption, TNF-␣ may
diminish glucose absorption in the proximal nephron. Injection
of TNF-␣ (1 mg/kg, bolus) decreases expression of sodium
glucose transporters SGLT2 and SGLT3 and Na-K-ATPase
within 12 h; however, it also increases Glut1 and SGLT1 in the
kidney. The increase in Glut1 and SGLT1 may occur as a
compensatory response to the reduced intracellular glucose
levels resulting from 1) decreased glucose entry due to reduc-
tions in SGLT2 and 3, and 2) the lower Na gradient due to
reduced Na-K-ATPase (125).
Renal Injury
Even though inhibition of transport could be interpreted as
protecting the kidney from injury, the majority of the literature
indicates that TNF-␣ induces renal damage. In part, this is
undoubtedly due to diminished renal perfusion such as seen in
sepsis (84, 127). It is also due in part to recruitment of immune
cells into the kidney, releasing cytokines that cause inflamma-
tion and cell death (169). Finally, it is also likely due to direct
actions of TNF-␣ on renal cells (65, 102).
TNFR1 contains a death domain, and thus the proapoptotic
actions of TNF-␣ have been mainly attributed to this receptor
(138, 64). TNFR1 interacts with the adaptor protein TNF recep-
tor-associated death domain (TRADD) through TNFR1-DD (59),
leading to recruitment of TNF receptor-associated factor 2
(TRAF2; Ref. 133). TRAF2 then interacts with the E3 ubiquitin
ligases “cellular inhibitor of apoptosis” (c-IAP) 1 and 2 to form
the membrane-bound complex I (93). c-IAP polyubiquitinates
chains of RIP1, which is essential for recruitment of transforming
growth factor-activated kinase 1 (TAK1) and activation of inhib-
itor of kappa B (I␬B) kinase (I␬K; Ref. 29). I␬K phosphorylates
I␬B, which is then degraded via the ubiquitin-proteasome path-
way, allowing NF-␬B to translocate to the nucleus where it
initiates gene transcription targeting anti-apoptotic genes like
c-FLIP, c-IAP-1 and 2, and TRAF1 and 2. Additionally, associ-
ation of RIP1 and TRAF-2 with TNFR1 can lead to activation of
mitogen-activated protein kinase kinase kinase 1 (MEKKK-1)
and c-Jun NH2-terminal kinases (JNK), which phosphorylate and
activate c-Jun, a member of the transcription factor complex
activator protein 1. Prolonged JNK activation mediates protea-
somal degradation of c-FLIP and activation of caspase-8, leading
to apoptosis (23, 135). TNF-␣ also activates apoptosis signaling
kinase-1 (ASK1) via TNFR1 by inducing ASK1-interacting pro-
tein-1, which promotes ASK1 dissociation from the adaptor pro-
tein 14 –3-3, phosphorylation at the stimulatory site threonine 845

TNF AND RENAL FUNCTION
(ASK1pThr845), and dephosphorylation of ASK1 at the inhibi-
tory site serine 967 (86, 143, 166, 167).
In the normal kidney, strong staining for phospho-serine 967
ASK1 (ASK1pser967, the inhibitory site) colocalized with
TNFR1 in glomerular and endothelial cells from peritubular
capillaries, whereas coexpression of TNFR1 and ASK1pThr845
(the stimulatory site) was not found. In contrast, in renal
allografts with acute cellular rejection, active ASK1pThr845
was strong in endothelial cells from glomerular and peritubular
capillaries and in some tubular epithelial cells, whereas
ASK1pSer967 was not detected. Similarly, in renal allografts
with acute tubular necrosis, ASK1pSer967 was diminished but
some tubular epithelial cells expressed a strong signal for
ASK1pThre845. This pattern of expression was also found in
normal kidney tissue treated with a TNFR1-specific activator;
however, when a TNFR2-specific activator was used, both
TNFR1 and ASK1pSer967 were elevated (9).
In contrast to TNFR1, activation of TNFR2 is associated
with both apoptosis and cell survival. TNFR2 interacts with
TRAF1 and 2, leading to RIP/c-IAP-induced activation of
NF-␬B (78, 120). Therefore, TNFR2 has been mainly associ-
ated with cell proliferation and survival (137). However, stud-
ies have shown a proapoptotic or cytotoxic function of TNFR2
activation (54, 67), and various models including TNFR2-
mediated activation of TNFR1 (107), cytosolic depletion of
c-IAP (39), and TNFR2-induced downregulation of NF-␬B
(46) have been proposed. A proapoptotic function for TNFR2
has been posited based on the fact that both TNFR2 and the
complement molecule C3 were upregulated in glomerulonephritic
kidneys and this was significantly reduced in TNFR2 KO mice,
suggesting that TNFR2 can activate complement (153). TNFR2
also activates endothelial/epithelial tyrosine kinase (Etk), which
has been linked to regulation of epithelial cell junctions (52),
whereas in endothelial cells it is involved in TNF-induced angio-
genic events (104) and mediates activation of PI3K and Akt (168).
TNFR2-induced activation of Etk is TRAF2 independent. Bind-
ing of TNF-␣ to TNFR2 induces Etk unfolding, phosphorylation,
and activation (104). In normal kidneys, TNFR2 was confined to
cells in the glomeruli and interstitium, with a strong signal for Etk
in glomerular endothelial cells. In renal allografts with acute
cellular rejection or acute tubular necrosis, a strong signal for
TNFR2 and Etkp was seen in most tubular epithelial cells. Similar
observations were made when kidney tissue cultures were treated
with a TNFR2-specific activator. Incubating kidney tissue with
this activator also increased proliferation of tubular epithelial cells
expressing Etkp, and this effect was more pronounced than when
a TNFR1-specific activator was used (9).
Finally, circulating levels of TNFR play an important role in
determining the severity of certain conditions, and therefore,
TNFR levels should be reported. In this regard, both Gohda et
al. (42) and Niewczas et al. (100) reported a strong positive
correlation between circulating TNFR1 and TNFR2 with pro-
gression to chronic kidney disease in type 1 diabetes and
end-stage renal disease in type 2 diabetes. This correlation was
independent of other markers, including circulating TNF-␣,
blood pressure, albuminuria, and GFR. These authors reported
that plasma concentrations of TNFR1 and 2 were clinical
predictors of end-stage renal disease and chronic kidney dis-
ease; however, they did not assess whether elevated circulating
TNFRs were the cause or the consequence of a dire outcome.
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Review
F1237
Concluding Remarks
The discrepancy between blood pressure-lowering effects and
prohypertensive actions of TNF-␣ is still a matter for debate but
is likely the result of many variables. For example, the TNF-␣
levels in plasma, the type of immune response (innate vs. adap-
tive), and the extent of the response (moderate vs. exaggerated)
can determine whether blood pressure is increased or a shock
response takes place. In general, plasma TNF-␣ levels in endo-
toxemic shock increase rapidly by 10-fold or more, whereas in
hypertension or heart failure TNF-␣ levels are increased 1- to
2-fold. Similarly, animal models mimicking sepsis are infused
with a bolus of 0.01 to 1 mg/kg TNF-␣, whereas the doses used
to induce hypertension in pregnant rats or TNF-␣ KO mice treated
with ANG II are 0.5 ␮g/kg or lower and are maintained for days.
This may mean that at high doses TNF-␣ has nonspecific effects
or activates signaling cascades leading to hypotension that sur-
passes its hypertensive actions. Alternatively, the nonreceptor-
mediated actions of TNF-␣, which are due to the presence of a
lectin-like domain in human TNF-␣, could be activated at high
doses. This domain, although far removed from the receptor
binding site, nevertheless recognizes oligosaccharides and medi-
ates some TNF-␣ actions like trypanolytic activity (88). In addi-
tion, sudden and exaggerated activation of the innate immune
response, with massive increases in macrophage and neutrophil
infiltration, seems to result in a shock state and leads to hypoten-
sion. In contrast, more moderate and chronic activation of the
adaptive immune response with participation of macrophages and
lymphocytes contributes to slowly developing renal damage, in-
creased NaCl retention, and hypertension.
One of the problems in dissecting the prohypertensive vs.
prohypotensive actions of TNF-␣ is that the approaches uti-
lized to block TNF-␣ differ in their side effects. The use of
chimeric proteins as opposed to antibodies to block the actions
of TNF or the use of a KO mouse model could explain why
TNF-␣ seems to be protective in some studies but detrimental
in others. Depending on which portion of the TNFR is con-
served during anti-TNF treatment, it may or may not induce
complement deposition and a cytotoxic reaction. In addition,
while KO models provide a promising tool to study the role of
certain genes in disease, they may also generate misleading
results. Impaired development of germinal centers and follic-
ular dendritic cell networks in secondary lymphoid organs has
been observed in TNF-␣ and TNFR1 KO mice (75, 82, 106).
Moreover, overexpression of TNFR1 in TNFR2 KO mice and
elevated TNFR2 in TNFR1 KO has been shown: thus a
seemingly protective role of TNFR1 that is absent in TNFR1
KO might be simply due to overexpression of TNFR2. Simi-
larly, a detrimental response in TNF-␣ or TNFR1 KO could be
attributable to their inability to handle infections, not the
absence of the direct effects of TNF on ion transport or blood
pressure. Finally, membrane-bound TNF effects, which have
been very poorly explored, could also confuse results.
Overall, blockade of TNF-␣ during hypertension seems to
provide a beneficial outcome, while handling the development
of autoimmune diseases in patients treated with TNF-neutral-
izing agents is not a trivial undertaking (75). On the other hand,
the battle between lowering TNF-␣ levels in septic shock and
stimulating the immune system to fight the infection still
represents a clinical challenge. Therefore, the discovery of
specific mediators of TNF-induced increases and decreases in
Review
F1238 TNF AND RENAL FUNCTION
blood pressure would represent a great advance in the gener-
ation of effective alternate treatments for hypertension and
shock-induced hypotension.
GRANTS
This work was supported by grants from the National Institutes of Health
(HL-028982, HL-070985, and HL-090550; to J. L. Garvin) and from the
American Heart Association (11PRE7510005; to V.D. Ramseyer).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: V.R. prepared figures; V.R. drafted manuscript; V.R.
and J.L.G. edited and revised manuscript; V.R. and J.L.G. approved final
version of manuscript.
REFERENCES
1. Abdullah HI, Pedraza PL, Hao S, Rodland KD, McGiff JC, Ferreri
NR. NFAT regulates calcium-sensing receptor-mediated TNF produc-
tion. Am J Physiol Renal Physiol 290: F1110 –F1117, 2006.
2. Abdullah HI, Pedraza PL, McGiff JC, Ferreri NR. Calcium-sensing
receptor signaling pathways in medullary thick ascending limb cells
mediate COX-2-derived PGE2 production: functional significance. Am J
Physiol Renal Physiol 295: F1082–F1089, 2008.
3. Abdullah HI, Pedraza PL, McGiff JC, Ferreri NR. CaR activation
increases TNF production by mTAL cells via a Gi-dependent mecha-
nism. Am J Physiol Renal Physiol 294: F345–F354, 2008.
4. Abraham E. Why immunomodulatory therapies have not worked in
sepsis. Intensive Care Med 25: 556 –566, 1999.
5. Adembri C, Sgambati E, Vitali L, Selmi V, Margheri M, Tani A,
Bonaccini L, Nosi D, Caldini AL, Formigli L, De Gaudio AR. Sepsis
induces albuminuria and alterations in the glomerular filtration barrier: a
morphofunctional study in the rat. Crit Care 15: R277, 2011.
6. Affres H, Perez J, Hagege J, Fouqueray B, Kornprobst M, Ardaillou
R, Baud L. Desferrioxamine regulates tumor necrosis factor release in
mesangial cells. Kidney Int 39: 822–830, 1991.
7. Aki K, Shimizu A, Masuda Y, Kuwahara N, Arai T, Ishikawa A,
Fujita E, Mii A, Natori Y, Fukunaga Y, Fukuda Y. ANG II receptor
blockade enhances anti-inflammatory macrophages in anti-glomerular
basement membrane glomerulonephritis. Am J Physiol Renal Physiol
298: F870 –F882, 2010.
8. Al-Lamki RS, Wang J, Skepper JN, Thiru S, Pober JS, Bradley JR.
Expression of tumor necrosis factor receptors in normal kidney and
rejecting renal transplants. Lab Invest 81: 1503–1515, 2001.
9. Al-Lamki RS, Wang J, Vandenabeele P, Bradley JA, Thiru S, Luo D,
Min W, Pober JS, Bradley JR. TNFR1- and TNFR2-mediated signal-
ing pathways in human kidney are cell type-specific and differentially
contribute to renal injury. FASEB J 19: 1637–1645, 2005.
10. Alexander BT, Cockrell KL, Massey MB, Bennett WA, Granger JP.
Tumor necrosis factor-alpha-induced hypertension in pregnant rats re-
sults in decreased renal neuronal nitric oxide synthase expression. Am J
Hypertens 15: 170 –175, 2002.
11. Bao HF, Zhang ZR, Liang YY, Ma JJ, Eaton DC, Ma HP. Ceramide
mediates inhibition of the renal epithelial sodium channel by tumor
necrosis factor-alpha through protein kinase C. Am J Physiol Renal
Physiol 293: F1178 –F1186, 2007.
12. Battula S, Hao S, Pedraza PL, Stier CT, Ferreri NR. Tumor necrosis
factor-alpha is an endogenous inhibitor of Na⫹-K⫹-2Cl⫺ cotransporter
(NKCC2) isoform A in the thick ascending limb. Am J Physiol Renal
Physiol 301: F94 –F100, 2011.
13. Baud L, Fouqueray B, Philippe C, Amrani A. Tumor necrosis factor
alpha and mesangial cells. Kidney Int 41: 600 –603, 1992.
14. Baud L, Oudinet JP, Bens M, Noe L, Peraldi MN, Rondeau E,
Etienne J, Ardaillou R. Production of tumor necrosis factor by rat
mesangial cells in response to bacterial lipopolysaccharide. Kidney Int
35: 1111–1118, 1989.
15. Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison
J, Ulevitch R, Cerami A. Identity of tumour necrosis factor and the
macrophage-secreted factor cachectin. Nature 316: 552–554, 1985.
AJP-Renal Physiol • doi:10.1152/ajprenal.00557.2012 • www.ajprenal.org
Downloaded from www.physiology.org/journal/ajprenal by ${individualUser.givenNames} ${individualUser.surname} (115.178.202.039) on December 25, 2017.
Copyright © 2013 American Physiological Society. All rights reserved.
16. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson
MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N,
Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson
RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase disinteg-
rin that releases tumour-necrosis factor-alpha from cells. Nature 385:
729 –733, 1997.
17. Bucher M, Kees F, Taeger K, Kurtz A. Cytokines down-regulate
alpha1-adrenergic receptor expression during endotoxemia. Crit Care
Med 31: 566 –571, 2003.
18. Burow ME, Weldon CB, Collins-Burow BM, Ramsey N, McKee A,
Klippel A, McLachlan JA, Clejan S, Beckman BS. Cross-talk between
phosphatidylinositol 3-kinase and sphingomyelinase pathways as a
mechanism for cell survival/death decisions. J Biol Chem 275: 9628 –
9635, 2000.
19. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An
endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl
Acad Sci USA 72: 3666 –3670, 1975.
20. Castillo A, Islam MT, Prieto MC, Majid DS. Tumor necrosis factor-
alpha receptor type 1, not type 2, mediates its acute responses in the
kidney. Am J Physiol Renal Physiol 302: F1650 –F1657, 2012.
21. Castrop H, Schnermann J. Isoforms of renal Na-K-2Cl cotransporter
NKCC2: expression and functional significance. Am J Physiol Renal
Physiol 295: F859 –F866, 2008.
22. Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. A
domain in TNF receptors that mediates ligand-independent receptor
assembly and signaling. Science 288: 2351–2354, 2000.
23. Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K,
Liu YC, Karin M. The E3 ubiquitin ligase itch couples JNK activation
to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell
124: 601–613, 2006.
24. Chen CC, Pedraza PL, Hao S, Stier CT, Ferreri NR. TNFR1-deficient
mice display altered blood pressure and renal responses to ANG II
infusion. Am J Physiol Renal Physiol 299: F1141–F1150, 2010.
25. Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreac-
tive cytokines in women with preeclampsia. Am J Reprod Immunol 40:
102–111, 1998.
26. Cunningham PN, Dyanov HM, Park P, Wang J, Newell KA, Quigg
RJ. Acute renal failure in endotoxemia is caused by TNF acting directly
on TNF receptor-1 in kidney. J Immunol 168: 5817–5823, 2002.
27. De PG, Castellano G, Del PA, Sozzani S, Fiore N, Loverre A,
Parmentier M, Gesualdo L, Grandaliano G, Schena FP. The possible
role of ChemR23/Chemerin axis in the recruitment of dendritic cells in
lupus nephritis. Kidney Int 79: 1228 –1235, 2011.
28. Declercq W, Denecker G, Fiers W, Vandenabeele P. Cooperation of
both TNF receptors in inducing apoptosis: involvement of the TNF
receptor-associated factor binding domain of the TNF receptor 75. J
Immunol 161: 390 –399, 1998.
29. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ. Activation of IKK by
TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin
binding by NEMO. Mol Cell 22: 245–257, 2006.
30. Ebenezer PJ, Mariappan N, Elks CM, Haque M, Francis J. Diet-
induced renal changes in Zucker rats are ameliorated by the superoxide
dismutase mimetic TEMPOL. Obesity (Silver Spring) 17: 1994 –2002,
2009.
31. Eitle E, Hiranyachattada S, Wang H, Harris PJ. Inhibition of proxi-
mal tubular fluid absorption by nitric oxide and atrial natriuretic peptide
in rat kidney. Am J Physiol Cell Physiol 274: C1075–C1080, 1998.
32. Elmarakby AA, Quigley JE, Imig JD, Pollock JS, Pollock DM.
TNF-alpha inhibition reduces renal injury in DOCA-salt hypertensive
rats. Am J Physiol Regul Integr Comp Physiol 294: R76 –R83, 2008.
33. Elmarakby AA, Quigley JE, Pollock DM, Imig JD. Tumor necrosis
factor alpha blockade increases renal Cyp2c23 expression and slows the
progression of renal damage in salt-sensitive hypertension. Hypertension
47: 557–562, 2006.
34. Escalante BA, Ferreri NR, Dunn CE, McGiff JC. Cytokines affect ion
transport in primary cultured thick ascending limb of Henle’s loop cells.
Am J Physiol Cell Physiol 266: C1568 –C1576, 1994.
35. Ferreri NR, Escalante BA, Zhao Y, An SJ, McGiff JC. Angiotensin II
induces TNF production by the thick ascending limb: functional impli-
cations. Am J Physiol Renal Physiol 274: F148 –F155, 1998.
36. Ferreri NR, Zhao Y, Takizawa H, McGiff JC. Tumor necrosis factor-
alpha-angiotensin interactions and regulation of blood pressure. J Hy-
pertens 15: 1481–1484, 1997.

TNF AND RENAL FUNCTION
37. Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney
JS, Lee AT, Kuo GC, Allison AC, Lowry SF. Antibodies to cachectin/
tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appear-
ance during lethal bacteremia. J Exp Med 170: 1627–1633, 1989.
38. Fornoni A, Ijaz A, Tejada T, Lenz O. Role of inflammation in diabetic
nephropathy. Curr Diabetes Rev 4: 10 –17, 2008.
39. Fotin-Mleczek M, Henkler F, Samel D, Reichwein M, Hausser A,
Parmryd I, Scheurich P, Schmid JA, Wajant H. Apoptotic crosstalk of
TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins
and accelerates TNF-R1-dependent activation of caspase-8. J Cell Sci
115: 2757–2770, 2002.
40. Fouqueray B, Philippe C, Herbelin A, Perez J, Ardaillou R, Baud L.
Cytokine formation within rat glomeruli during experimental endotox-
emia. J Am Soc Nephrol 3: 1783–1791, 1993.
41. Giamarellos-Bourboulis EJ. Immunomodulatory therapies for sepsis:
unexpected effects with macrolides. Int J Antimicrob Agents 32, Suppl 1:
S39 –S43, 2008.
42. Gohda T, Niewczas MA, Ficociello LH, Walker WH, Skupien J,
Rosetti F, Cullere X, Johnson AC, Crabtree G, Smiles AM, Mayadas
TN, Warram JH, Krolewski AS. Circulating TNF receptors 1 and 2
predict stage 3 CKD in type 1 diabetes. J Am Soc Nephrol 23: 516 –524,
2012.
43. Gomez-Guerrero C, Lopez-Armada MJ, Gonzalez E, Egido J. Sol-
uble IgA and IgG aggregates are catabolized by cultured rat mesangial
cells and induce production of TNF-alpha and IL-6, and proliferation. J
Immunol 153: 5247–5255, 1994.
44. Gomez-Sanchez EP, Zhou M, Gomez-Sanchez CE. Mineralocortico-
ids, salt and high blood pressure. Steroids 61: 184 –188, 1996.
45. Gonzalez-Villalobos RA, Seth DM, Satou R, Horton H, Ohashi N,
Miyata K, Katsurada A, Tran DV, Kobori H, Navar LG. Intrarenal
angiotensin II and angiotensinogen augmentation in chronic angiotensin
II-infused mice. Am J Physiol Renal Physiol 295: F772–F779, 2008.
46. Grech AP, Gardam S, Chan T, Quinn R, Gonzales R, Basten A,
Brink R. Tumor necrosis factor receptor 2 (TNFR2) signaling is nega-
tively regulated by a novel, carboxyl-terminal TNFR-associated factor 2
(TRAF2)-binding site. J Biol Chem 280: 31572–31581, 2005.
47. Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B,
Georgopoulos S, Lesslauer W, Kollias G, Pfizenmaier K, Scheurich
P. The transmembrane form of tumor necrosis factor is the prime
activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83:
793–802, 1995.
48. Grell M, Wajant H, Zimmermann G, Scheurich P. The type 1 receptor
(CD120a) is the high-affinity receptor for soluble tumor necrosis factor.
Proc Natl Acad Sci USA 95: 570 –575, 1998.
49. Grinevich V, Knepper MA, Verbalis J, Reyes I, Aguilera G. Acute
endotoxemia in rats induces down-regulation of V2 vasopressin receptors
and aquaporin-2 content in the kidney medulla. Kidney Int 65: 54 –62,
2004.
50. Guo G, Morrissey J, McCracken R, Tolley T, Klahr S. Role of
TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive
nephropathy. Am J Physiol Renal Physiol 277: F766 –F772, 1999.
51. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S,
Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis
of angiotensin II induced hypertension and vascular dysfunction. J Exp
Med 204: 2449 –2460, 2007.
52. Hamm-Alvarez SF, Chang A, Wang Y, Jerdeva G, Lin HH, Kim KJ,
Ann DK. Etk/Bmx activation modulates barrier function in epithelial
cells. Am J Physiol Cell Physiol 280: C1657–C1668, 2001.
53. Hao S, Zhao H, Darzynkiewicz Z, Battula S, Ferreri NR. Expression
and function of NFAT5 in medullary thick ascending limb (mTAL) cells.
Am J Physiol Renal Physiol 296: F1494 –F1503, 2009.
54. Heller RA, Song K, Fan N, Chang DJ. The p70 tumor necrosis factor
receptor mediates cytotoxicity. Cell 70: 47–56, 1992.
55. Helms MN, Liu L, Liang YY, Al-Khalili O, Vandewalle A, Saxena S,
Eaton DC, Ma HP. Phosphatidylinositol 3,4,5-trisphosphate mediates
aldosterone stimulation of epithelial sodium channel (ENaC) and inter-
acts with gamma-ENaC. J Biol Chem 280: 40885–40891, 2005.
56. Herrera M, Hong NJ, Ortiz PA, Garvin JL. Endothelin-1 inhibits thick
ascending limb transport via Akt-stimulated nitric oxide production. J
Biol Chem 284: 1454 –1460, 2009.
57. Herrera M, Silva GB, Garvin JL. Angiotensin II stimulates thick
ascending limb superoxide production via protein kinase C(alpha)-de-
pendent NADPH oxidase activation. J Biol Chem 285: 21323–21328,
2010.
AJP-Renal Physiol • doi:10.1152/ajprenal.00557.2012 • www.ajprenal.org
Downloaded from www.physiology.org/journal/ajprenal by ${individualUser.givenNames} ${individualUser.surname} (115.178.202.039) on December 25, 2017.
Copyright © 2013 American Physiological Society. All rights reserved.
Review
F1239
58. Hocherl K, Schmidt C, Kurt B, Bucher M. Inhibition of NF-␬B
ameliorates sepsis-induced downregulation of aquaporin-2/V2 receptor
expression and acute renal failure in vivo. Am J Physiol Renal Physiol
298: F196 –F204, 2010.
59. Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein
TRADD signals cell death and NF-kappa B activation. Cell 81: 495–504,
1995.
60. Ichinose Y, Tsao JY, Fidler IJ. Destruction of tumor cells by mono-
kines released from activated human blood monocytes: evidence for
parallel and additive effects of IL-1 and TNF. Cancer Immunol Immu-
nother 27: 7–12, 1988.
61. Imaizumi T, Itaya H, Fujita K, Kudoh D, Kudoh S, Mori K,
Fujimoto K, Matsumiya T, Yoshida H, Satoh K. Expression of tumor
necrosis factor-alpha in cultured human endothelial cells stimulated with
lipopolysaccharide or interleukin-1alpha. Arterioscler Thromb Vasc Biol
20: 410 –415, 2000.
62. Irani RA, Zhang Y, Zhou CC, Blackwell SC, Hicks MJ, Ramin SM,
Kellems RE, Xia Y. Autoantibody-mediated angiotensin receptor acti-
vation contributes to preeclampsia through tumor necrosis factor-alpha
signaling. Hypertension 55: 1246 –1253, 2010.
63. Ito H, Ohshima A, Tsuzuki M, Ohto N, Takao K, Hijii C, Yanagawa
M, Ogasawara M, Nishioka K. Association of serum tumour necrosis
factor-alpha with serum low-density lipoprotein-cholesterol and blood
pressure in apparently healthy Japanese women. Clin Exp Pharmacol
Physiol 28: 188 –192, 2001.
64. Itoh N, Nagata S. A novel protein domain required for apoptosis.
Mutational analysis of human Fas antigen. J Biol Chem 268: 10932–
10937, 1993.
65. Izawa-Ishizawa Y, Ishizawa K, Sakurada T, Imanishi M, Miyamoto
L, Fujii S, Taira H, Kihira Y, Ikeda Y, Hamano S, Tomita S,
Tsuchiya K, Tamaki T. Angiotensin II receptor blocker improves tumor
necrosis factor-alpha-induced cytotoxicity via antioxidative effect in
human glomerular endothelial cells. Pharmacology 90: 324 –331, 2012.
66. Jevnikar AM, Brennan DC, Singer GG, Heng JE, Maslinski W,
Wuthrich RP, Glimcher LH, Kelley VE. Stimulated kidney tubular
epithelial cells express membrane associated and secreted TNF alpha.
Kidney Int 40: 203–211, 1991.
67. Ji W, Li Y, Wan T, Wang J, Zhang H, Chen H, Min W. Both
internalization and aip1 association are required for tumor necrosis factor
receptor 2-mediated JNK signaling. Arterioscler Thromb Vasc Biol 32:
2271–2279, 2012.
68. Kabore AF, Denis M, Bergeron MG. Association of nitric oxide
production by kidney proximal tubular cells in response to lipopolysac-
charide and cytokines with cellular damage. Antimicrob Agents Che-
mother 41: 557–562, 1997.
69. Kakiashvili E, Dan Q, Vandermeer M, Zhang Y, Waheed F, Pham
M, Szaszi K. The epidermal growth factor receptor mediates tumor
necrosis factor-alpha-induced activation of the ERK/GEF-H1/RhoA
pathway in tubular epithelium. J Biol Chem 286: 9268 –9279, 2011.
70. Kakiashvili E, Speight P, Waheed F, Seth R, Lodyga M, Tanimura S,
Kohno M, Rotstein OD, Kapus A, Szaszi K. GEF-H1 mediates tumor
necrosis factor-alpha-induced Rho activation and myosin phosphoryla-
tion: role in the regulation of tubular paracellular permeability. J Biol
Chem 284: 11454 –11466, 2009.
71. Karkar AM, Koshino Y, Cashman SJ, Dash AC, Bonnefoy J, Meager
A, Rees AJ. Passive immunization against tumour necrosis factor-alpha
(TNF-alpha) and IL-1 beta protects from LPS enhancing glomerular
injury in nephrotoxic nephritis in rats. Clin Exp Immunol 90: 312–318,
1992.
72. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R,
Lodato RF. NG-methyl-L-arginine inhibits tumor necrosis factor-in-
duced hypotension: implications for the involvement of nitric oxide. Proc
Natl Acad Sci USA 87: 3629 –3632, 1990.
73. Kim YK, Choi TR, Kwon CH, Kim JH, Woo JS, Jung JS. Beneficial
effect of pentoxifylline on cisplatin-induced acute renal failure in rabbits.
Ren Fail 25: 909 –922, 2003.
74. Kita T, Tanaka N, Nagano T. The immunocytochemical localization of
tumour necrosis factor and leukotriene in the rat kidney after treatment
with lipopolysaccharide. Int J Exp Pathol 74: 471–479, 1993.
75. Kollias G, Kontoyiannis D. Role of TNF/TNFR in autoimmunity:
specific TNF receptor blockade may be advantageous to anti-TNF treat-
ments. Cytokine Growth Factor Rev 13: 315–321, 2002.
Review
F1240 TNF AND RENAL FUNCTION
76. Kriegler M, Perez C, DeFay K, Albert I, Lu SD. A novel form of
TNF/cachectin is a cell surface cytotoxic transmembrane protein: rami-
fications for the complex physiology of TNF. Cell 53: 45–53, 1988.
77. Kumar A, Paladugu B, Mensing J, Kumar A, Parrillo JE. Nitric
oxide-dependent and -independent mechanisms are involved in TNF-␣-
induced depression of cardiac myocyte contractility. Am J Physiol Regul
Integr Comp Physiol 292: R1900 –R1906, 2007.
78. Laegreid A, Medvedev A, Nonstad U, Bombara MP, Ranges G,
Sundan A, Espevik T. Tumor necrosis factor receptor p75 mediates
cell-specific activation of nuclear factor kappa B and induction of human
cytomegalovirus enhancer. J Biol Chem 269: 7785–7791, 1994.
79. LaMarca B, Speed J, Fournier L, Babcock SA, Berry H, Cockrell K,
Granger JP. Hypertension in response to chronic reductions in uterine
perfusion in pregnant rats: effect of tumor necrosis factor-alpha blockade.
Hypertension 52: 1161–1167, 2008.
80. LaMarca BB, Bennett WA, Alexander BT, Cockrell K, Granger JP.
Hypertension produced by reductions in uterine perfusion in the pregnant
rat: role of tumor necrosis factor-alpha. Hypertension 46: 1022–1025,
2005.
81. LaMarca BB, Cockrell K, Sullivan E, Bennett W, Granger JP. Role
of endothelin in mediating tumor necrosis factor-induced hypertension in
pregnant rats. Hypertension 46: 82–86, 2005.
82. Le Hir M, Bluethmann H, Kosco-Vilbois MH, Müller M, di Padova
F, Moore M, Ryffel B, Eugster HP. Differentiation of follicular den-
dritic cells and full antibody responses require tumor necrosis factor
receptor-1 signaling. J Exp Med 183: 2367–2372, 1996.
83. Lee S, Kim W, Kang KP, Moon SO, Sung MJ, Kim DH, Kim HJ,
Park SK. Agonist of peroxisome proliferator-activated receptor-gamma,
rosiglitazone, reduces renal injury and dysfunction in a murine sepsis
model. Nephrol Dial Transplant 20: 1057–1065, 2005.
84. Legrand M, Bezemer R, Kandil A, Demirci C, Payen D, Ince C. The
role of renal hypoperfusion in development of renal microcirculatory
dysfunction in endotoxemic rats. Intensive Care Med 37: 1534 –1542,
2011.
85. Leon CG, Tory R, Jia J, Sivak O, Wasan KM. Discovery and
development of toll-like receptor 4 (TLR4) antagonists: a new paradigm
for treating sepsis and other diseases. Pharm Res 25: 1751–1761, 2008.
86. Liu Y, Yin G, Surapisitchat J, Berk BC, Min W. Laminar flow inhibits
TNF-induced ASK1 activation by preventing dissociation of ASK1 from
its inhibitor 14 –3-3. J Clin Invest 107: 917–923, 2001.
87. Lucas R, Garcia I, Donati YR, Hribar M, Mandriota SJ, Giroud C,
Buurman WA, Fransen L, Suter PM, Nunez G, Pepper MS, Grau
GE. Both TNF receptors are required for direct TNF-mediated cytotox-
icity in microvascular endothelial cells. Eur J Immunol 28: 3577–3586,
1998.
88. Lucas R, Magez S, De LR, Fransen L, Scheerlinck JP, Rampelberg
M, Sablon E, De BP. Mapping the lectin-like activity of tumor necrosis
factor. Science 263: 814 –817, 1994.
89. Luettig B, Decker T, Lohmann-Matthes ML. Evidence for the exis-
tence of two forms of membrane tumor necrosis factor: an integral
protein and a molecule attached to its receptor. J Immunol 143: 4034 –
4038, 1989.
90. Macica CM, Escalante BA, Conners MS, Ferreri NR. TNF production
by the medullary thick ascending limb of Henle’s loop. Kidney Int 46:
113–121, 1994.
91. Markewitz BA, Michael JR, Kohan DE. Cytokine-induced expression
of a nitric oxide synthase in rat renal tubule cells. J Clin Invest 91:
2138 –2143, 1993.
92. McDonnell PC, Kumar S, Rabson AB, Gelinas C. Transcriptional
activity of rel family proteins. Oncogene 7: 163–170, 1992.
93. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis
via two sequential signaling complexes. Cell 114: 181–190, 2003.
94. Misseri R, Meldrum DR, Dagher P, Hile K, Rink RC, Meldrum KK.
Unilateral ureteral obstruction induces renal tubular cell production of
tumor necrosis factor-alpha independent of inflammatory cell infiltration.
J Urol 172: 1595–1599, 2004.
95. Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM. Tonicity-
responsive enhancer binding protein, a rel-like protein that stimulates
transcription in response to hypertonicity. Proc Natl Acad Sci USA 96:
2538 –2542, 1999.
96. Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E,
Hampich F, Fiebeler A, Ju X, Finckenberg P, Theuer J, Viedt C,
Kreuzer J, Heidecke H, Haller H, Zenke M, Luft FC. Immunosup-
AJP-Renal Physiol • doi:10.1152/ajprenal.00557.2012 • www.ajprenal.org
Downloaded from www.physiology.org/journal/ajprenal by ${individualUser.givenNames} ${individualUser.surname} (115.178.202.039) on December 25, 2017.
Copyright © 2013 American Physiological Society. All rights reserved.
pressive treatment protects against angiotensin II-induced renal damage.
Am J Pathol 161: 1679 –1693, 2002.
97. Naikawadi RP, Cheng N, Vogel SM, Qian F, Wu D, Malik AB, Ye
RD. A critical role for phosphatidylinositol (3,4,5)-trisphosphate-depen-
dent Rac exchanger 1 in endothelial junction disruption and vascular
hyperpermeability. Circ Res 111: 1517–1527, 2012.
98. Nakamura A, Johns EJ, Imaizumi A, Niimi R, Yanagawa Y, Koh-
saka T. Role of angiotensin II-induced cAMP in mesangial TNF-alpha
production. Cytokine 19: 47–51, 2002.
99. Neale TJ, Ruger BM, Macaulay H, Dunbar PR, Hasan Q, Bourke A,
Murray-McIntosh RP, Kitching AR. Tumor necrosis factor-alpha is
expressed by glomerular visceral epithelial cells in human membranous
nephropathy. Am J Pathol 146: 1444 –1454, 1995.
100. Niewczas MA, Gohda T, Skupien J, Smiles AM, Walker WH, Rosetti
F, Cullere X, Eckfeldt JH, Doria A, Mayadas TN, Warram JH,
Krolewski AS. Circulating TNF receptors 1 and 2 predict ESRD in type
2 diabetes. J Am Soc Nephrol 23: 507–515, 2012.
101. Noiri E, Kuwata S, Nosaka K, Tokunaga K, Juji T, Shibata Y,
Kurokawa K. Tumor necrosis factor-alpha mRNA expression in lipopo-
lysaccharide-stimulated rat kidney. Chronological analysis of localiza-
tion. Am J Pathol 144: 1159 –1166, 1994.
102. Ortiz A, Lorz C, Justo P, Catalan MP, Egido J. Contribution of
apoptotic cell death to renal injury. J Cell Mol Med 5: 18 –32, 2001.
103. Ortiz PA, Hong NJ, Wang D, Garvin JL. Gene transfer of eNOS to the
thick ascending limb of eNOS-KO mice restores the effects of L-arginine
on NaCl absorption. Hypertension 42: 674 –679, 2003.
104. Pan S, An P, Zhang R, He X, Yin G, Min W. Etk/Bmx as a tumor
necrosis factor receptor type 2-specific kinase: role in endothelial cell
migration and angiogenesis. Mol Cell Biol 22: 7512–7523, 2002.
105. Parameswaran N, Patial S. Tumor necrosis factor-alpha signaling in
macrophages. Crit Rev Eukaryot Gene Expr 20: 87–103, 2010.
106. Pfeffer K. Biological functions of tumor necrosis factor cytokines and
their receptors. Cytokine Growth Factor Rev 14: 185–191, 2003.
107. Pinckard JK, Sheehan KC, Schreiber RD. Ligand-induced formation
of p55 and p75 tumor necrosis factor receptor heterocomplexes on intact
cells. J Biol Chem 272: 10784 –10789, 1997.
108. Plato CF, Garvin JL. ␣2-Adrenergic-mediated tubular NO production
inhibits thick ascending limb chloride absorption. Am J Physiol Renal
Physiol 281: F679 –F686, 2001.
109. Plato CF, Pollock DM, Garvin JL. Endothelin inhibits thick ascending
limb chloride flux via ETB receptor-mediated NO release. Am J Physiol
Renal Physiol 279: F326 –F333, 2000.
110. Plato CF, Shesely EG, Garvin JL. eNOS mediates L-arginine-induced
inhibition of thick ascending limb chloride flux. Hypertension 35: 319 –
323, 2000.
111. Pocsik E, Duda E, Wallach D. Phosphorylation of the 26 kDa TNF
precursor in monocytic cells and in transfected HeLa cells. J Inflamm 45:
152–160, 1995.
112. Qiu P, Cui X, Barochia A, Li Y, Natanson C, Eichacker PQ. The
evolving experience with therapeutic TNF inhibition in sepsis: consid-
ering the potential influence of risk of death. Expert Opin Investig Drugs
20: 1555–1564, 2011.
113. Ramesh G, Brian RW. Cisplatin increases TNF-alpha mRNA stability
in kidney proximal tubule cells. Ren Fail 28: 583–592, 2006.
114. Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine
expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 110:
835–842, 2002.
115. Ramesh G, Reeves WB. Inflammatory cytokines in acute renal failure.
Kidney Int Suppl S56 –S61, 2004.
116. Ramseyer VD, Hong NJ, Garvin JL. Tumor necrosis factor alpha
decreases nitric oxide synthase type 3 expression primarily via Rho/Rho
kinase in the thick ascending limb. Hypertension 59: 1145–1150, 2012.
117. Rees DD, Monkhouse JE, Cambridge D, Moncada S. Nitric oxide and
the haemodynamic profile of endotoxin shock in the conscious mouse. Br
J Pharmacol 124: 540 –546, 1998.
118. Roczniak A, Burns KD. Nitric oxide stimulates guanylate cyclase and
regulates sodium transport in rabbit proximal tubule. Am J Physiol Renal
Fluid Electrolyte Physiol 270: F106 –F115, 1996.
119. Rosa AC, Rattazzi L, Miglio G, Collino M, Fantozzi R. Angiotensin II
induces tumor necrosis factor-alpha expression and release from cultured
human podocytes. Inflamm Res 61: 311–317, 2012.
120. Rothe M, Wong SC, Henzel WJ, Goeddel DV. A novel family of
putative signal transducers associated with the cytoplasmic domain of the
75 kDa tumor necrosis factor receptor. Cell 78: 681–692, 1994.

TNF AND RENAL FUNCTION
121. Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J,
Mezzano S, Egido J. Angiotensin II regulates the synthesis of proin-
flammatory cytokines and chemokines in the kidney. Kidney Int Suppl
S12–S22, 2002.
122. Saftlas AF, Olson DR, Franks AL, Atrash HK, Pokras R. Epidemi-
ology of preeclampsia and eclampsia in the United States, 1979 –1986.
Am J Obstet Gynecol 163: 460 –465, 1990.
123. Satou R, Miyata K, Katsurada A, Navar LG, Kobori H. Tumor
necrosis factor-␣ suppresses angiotensinogen expression through forma-
tion of a p50/p50 homodimer in human renal proximal tubular cells. Am
J Physiol Cell Physiol 299: C750 –C759, 2010.
124. Schmidt C, Hocherl K, Bucher M. Cytokine-mediated regulation of
urea transporters during experimental endotoxemia. Am J Physiol Renal
Physiol 292: F1479 –F1489, 2007.
125. Schmidt C, Hocherl K, Bucher M. Regulation of renal glucose trans-
porters during severe inflammation. Am J Physiol Renal Physiol 292:
F804 –F811, 2007.
126. Schmidt C, Hocherl K, Schweda F, Kurtz A, Bucher M. Regulation of
renal sodium transporters during severe inflammation. J Am Soc Nephrol
18: 1072–1083, 2007.
127. Shahid M, Francis J, Majid DS. Tumor necrosis factor-␣ induces renal
vasoconstriction as well as natriuresis in mice. Am J Physiol Renal
Physiol 295: F1836 –F1844, 2008.
128. Silva GB, Garvin JL. Angiotensin II-dependent hypertension increases
Na transport-related oxygen consumption by the thick ascending limb.
Hypertension 52: 1091–1098, 2008.
129. Singh P, Bahrami L, Castillo A, Majid DS. TNF-␣ type 2 receptor
mediates renal inflammatory response to chronic angiotensin II admin-
istration with high salt intake in mice. Am J Physiol Renal Physiol 304:
F991–F999, 2013.
130. Sonkar GK, Singh RG. Evaluation of serum tumor necrosis factor alpha
and its correlation with histology in chronic kidney disease, stable renal
transplant and rejection cases. Saudi J Kidney Dis Transpl 20: 1000 –
1004, 2009.
131. Sriramula S, Haque M, Majid DS, Francis J. Involvement of tumor
necrosis factor-alpha in angiotensin II-mediated effects on salt appetite,
hypertension, and cardiac hypertrophy. Hypertension 51: 1345–1351,
2008.
132. Stoos BA, Garcia NH, Garvin JL. Nitric oxide inhibits sodium reab-
sorption in the isolated perfused cortical collecting duct. J Am Soc
Nephrol 6: 89 –94, 1995.
133. Takeuchi M, Rothe M, Goeddel Anatomy of TRAF2 DV. Distinct
domains for nuclear factor-kappaB activation and association with tumor
necrosis factor signaling proteins. J Biol Chem 271: 19935–19942, 1996.
134. Tan X, He W, Liu Y. Combination therapy with paricalcitol and
trandolapril reduces renal fibrosis in obstructive nephropathy. Kidney Int
76: 1248 –1257, 2009.
135. Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M, Lin A.
Inhibition of JNK activation through NF-kappaB target genes. Nature
414: 313–317, 2001.
136. Tang P, Hung MC, Klostergaard J. Human pro-tumor necrosis factor
is a homotrimer. Biochemistry 35: 8216 –8225, 1996.
137. Tartaglia LA, Goeddel DV, Reynolds C, Figari IS, Weber RF, Fendly
BM, Palladino MA Jr. Stimulation of human T-cell proliferation by
specific activation of the 75-kDa tumor necrosis factor receptor. J
Immunol 151: 4637–4641, 1993.
138. Tartaglia LA, Weber RF, Figari IS, Reynolds C, Palladino MA Jr,
Goeddel DV. The two different receptors for tumor necrosis factor
mediate distinct cellular responses. Proc Natl Acad Sci USA 88: 9292–
9296, 1991.
139. Therrien FJ, Agharazii M, Lebel M, Lariviere R. Neutralization of
tumor necrosis factor-alpha reduces renal fibrosis and hypertension in
rats with renal failure. Am J Nephrol 36: 151–161, 2012.
140. Tikkanen I, Uhlenius N, Tikkanen T, Miettinen A, Tornroth T,
Fyhrquist F, Holthofer H. Increased renal expression of cytokines and
growth factors induced by DOCA-NaCl treatment in Heymann nephritis.
Nephrol Dial Transplant 10: 2192–2198, 1995.
141. Timoshanko JR, Sedgwick JD, Holdsworth SR, Tipping PG. Intrinsic
renal cells are the major source of tumor necrosis factor contributing to
renal injury in murine crescentic glomerulonephritis. J Am Soc Nephrol
14: 1785–1793, 2003.
142. Tipping PG, Leong TW, Holdsworth SR. Tumor necrosis factor
production by glomerular macrophages in anti-glomerular basement
membrane glomerulonephritis in rabbits. Lab Invest 65: 272–279, 1991.
AJP-Renal Physiol • doi:10.1152/ajprenal.00557.2012 • www.ajprenal.org
Downloaded from www.physiology.org/journal/ajprenal by ${individualUser.givenNames} ${individualUser.surname} (115.178.202.039) on December 25, 2017.
Copyright © 2013 American Physiological Society. All rights reserved.
Review
F1241
143. Tobiume K, Saitoh M, Ichijo H. Activation of apoptosis signal-regu-
lating kinase 1 by the stress-induced activating phosphorylation of
pre-formed oligomer. J Cell Physiol 191: 95–104, 2002.
144. Todorov V, Muller M, Schweda F, Kurtz A. Tumor necrosis factor-␣
inhibits renin gene expression. Am J Physiol Regul Integr Comp Physiol
283: R1046 –R1051, 2002.
145. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark
IW, Hariri RJ, Fahey TJ, III, Zentella A, Albert JD. Shock and tissue
injury induced by recombinant human cachectin. Science 234: 470–474, 1986.
146. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC,
Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies pre-
vent septic shock during lethal bacteraemia. Nature 330: 662–664, 1987.
147. Tran LT, MacLeod KM, McNeill JH. Chronic etanercept treatment
prevents the development of hypertension in fructose-fed rats. Mol Cell
Biochem 330: 219 –228, 2009.
148. Utsumi T, Takeshige T, Tanaka K, Takami K, Kira Y, Klostergaard
J, Ishisaka R. Transmembrane TNF (pro-TNF) is palmitoylated. FEBS
Lett 500: 1–6, 2001.
149. Van den Berg DT, de Kloet ER, de JW. Central effects of mineralo-
corticoid antagonist RU-28318 on blood pressure of DOCA-salt hyper-
tensive rats. Am J Physiol Endocrinol Metab 267: E927–E933, 1994.
150. Van Zee KJ, Moldawer LL, Oldenburg HS, Thompson WA,
Stackpole SA, Montegut WJ, Rogy MA, Meschter C, Gallati H,
Schiller CD, Richter WF, Loetscher H, Ashkenazi A, Chamow
SM, Wurm F, Calvano SE, Lowry SF, Lesslauer W. Protection
against lethal Escherichia coli bacteremia in baboons (Papio anubis)
by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion
protein, Ro 45–2081. J Immunol 156: 2221–2230, 1996.
151. Vandenabeele P, Declercq W, Beyaert R, Fiers W. Two tumour
necrosis factor receptors: structure and function. Trends Cell Biol 5:
392–399, 1995.
152. Venegas-Pont M, Manigrasso MB, Grifoni SC, LaMarca BB, Maric
C, Racusen LC, Glover PH, Jones AV, Drummond HA, Ryan MJ.
Tumor necrosis factor-alpha antagonist etanercept decreases blood pres-
sure and protects the kidney in a mouse model of systemic lupus
erythematosus. Hypertension 56: 643–649, 2010.
153. Vielhauer V, Stavrakis G, Mayadas TN. Renal cell-expressed TNF
receptor 2, not receptor 1, is essential for the development of glomeru-
lonephritis. J Clin Invest 115: 1199 –1209, 2005.
154. Vinciguerra M, Hasler U, Mordasini D, Roussel M, Capovilla M,
Ogier-Denis E, Vandewalle A, Martin PY, Feraille E. Cytokines and
sodium induce protein kinase A-dependent cell-surface Na,K-ATPase
recruitment via dissociation of NF-kappaB/IkappaB/protein kinase A
catalytic subunit complex in collecting duct principal cells. J Am Soc
Nephrol 16: 2576 –2585, 2005.
155. Wang D, An SJ, Wang WH, McGiff JC, Ferreri NR. CaR-mediated
COX-2 expression in primary cultured mTAL cells. Am J Physiol Renal
Physiol 281: F658 –F664, 2001.
156. Wang D, Pedraza PL, Abdullah HI, McGiff JC, Ferreri NR. Calcium-
sensing receptor-mediated TNF production in medullary thick ascending
limb cells. Am J Physiol Renal Physiol 283: F963–F970, 2002.
157. Wang T, Inglis FM, Kalb RG. Defective fluid and HCO⫺ 3 absorption in
proximal tubule of neuronal nitric oxide synthase-knockout mice. Am J
Physiol Renal Physiol 279: F518 –F524, 2000.
158. Wray GM, Coakley JH. Severe septic shock unresponsive to noradren-
aline. Lancet 346: 1604, 1995.
159. Wu X, Wittwer AJ, Carr LS, Crippes BA, DeLarco JE, Lefkowith
JB. Cytokine-induced neutrophil chemoattractant mediates neutrophil
influx in immune complex glomerulonephritis in rat. J Clin Invest 94:
337–344, 1994.
160. Wuthrich RP, Glimcher LH, Yui MA, Jevnikar AM, Dumas SE,
Kelley VE. MHC class II, antigen presentation and tumor necrosis factor
in renal tubular epithelial cells. Kidney Int 37: 783–792, 1990.
161. Yard BA, Daha MR, Kooymans-Couthino M, Bruijn JA, Paape ME,
Schrama E, van Es LA, van der Woude FJ. IL-1 alpha stimulated TNF
alpha production by cultured human proximal tubular epithelial cells.
Kidney Int 42: 383–389, 1992.
162. Yeo ES, Hwang JY, Park JE, Choi YJ, Huh KB, Kim WY. Tumor
necrosis factor (TNF-alpha) and C-reactive protein (CRP) are positively
associated with the risk of chronic kidney disease in patients with type 2
diabetes. Yonsei Med J 51: 519 –525, 2010.
163. Zager RA, Johnson AC, Hanson SY, Lund S. Ischemic proximal
tubular injury primes mice to endotoxin-induced TNF-␣ generation and
systemic release. Am J Physiol Renal Physiol 289: F289 –F297, 2005.
Review
F1242 TNF AND RENAL FUNCTION

164. Zager RA, Johnson AC, Hanson SY, Lund S. Acute nephrotoxic and
obstructive injury primes the kidney to endotoxin-driven cytokine/
chemokine production. Kidney Int 69: 1181–1188, 2006.
165. Zanotti-Cavazzoni SL, Hollenberg SM. Cardiac dysfunction in severe
sepsis and septic shock. Curr Opin Crit Care 15: 392–397, 2009.
166. Zhang L, Chen J, Fu H. Suppression of apoptosis signal-regulating
kinase 1-induced cell death by 14 –3-3 proteins. Proc Natl Acad Sci USA
96: 8511–8515, 1999.
167. Zhang R, He X, Liu W, Lu M, Hsieh JT, Min W. AIP1 mediates
TNF-alpha-induced ASK1 activation by facilitating dissociation of
ASK1 from its inhibitor 14 –3-3. J Clin Invest 111: 1933–1943, 2003.
168. Zhang R, Xu Y, Ekman N, Wu Z, Wu J, Alitalo K, Min W. Etk/Bmx
transactivates vascular endothelial growth factor 2 and recruits phospha-
tidylinositol 3-kinase to mediate the tumor necrosis factor-induced an-
giogenic pathway. J Biol Chem 278: 51267–51276, 2003.
169. Zhu L, Yang X, Ji Y, Chen W, Guan W, Zhou SF, Yu X. Up-regulated
renal expression of TNF-alpha signalling adapter proteins in lupus
glomerulonephritis. Lupus 18: 116 –127, 2009.
170. Zinman B, Hanley AJ, Harris SB, Kwan J, Fantus IG. Circulating
tumor necrosis factor-alpha concentrations in a native Canadian popula-
tion with high rates of type 2 diabetes mellitus. J Clin Endocrinol Metab
84: 272–278, 1999.

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