Tumor Necrosis Factor-␣ in the Kidney: Synthesis TNF-␣ production is augmented in proximal tubule cells in
and Secretion response to IL-1␣ but not IL-2 or IFN␥ (161). This increase is
inhibited by cycloheximide, suggesting that it is not due to
TNF-␣ IS A PROINFLAMMATORY cytokine that was originally
increased TNF shedding from the membrane but rather en-
described as antitumorigenic (19, 60) and produced by immune hanced protein synthesis.
cells like macrophages and lymphocytes (15, 105, 142); how- In the thick ascending limb, CaSR activation stimulates Gi
ever, further studies revealed it is also produced by endothelial and Gq protein (3); this activates phosphatidylinositol-specific
and epithelial cells (14, 43, 61, 66, 71, 98, 99, 101, 141, 160). phospholipase C, which in turn produces inositol triphosphate
TNF-␣ is expressed as a 26-kDa plasma membrane protein that and diacylglycerol. Inositol triphosphate increases intracellular
is secreted into the extracellular space by the metalloproteinase Ca, which forms a complex with calmodulin whereas diacyl-
TNF-␣-converting enzyme (TACE, also called a disintegrin glycerol activates protein kinase C (PKC). These two conver-
and metalloproteinase 17 or ADAM 17; Refs. 16, 76, 89). In gent cascades lead to activation of calcineurin. Activated
solution, this 17-kDa protein forms homotrimers and activates calcineurin dephosphorylates nuclear factor of activated T cells
two distinct receptors (151). Transmembrane TNF-␣ also (NFAT), allowing translocation of this transcription factor to
forms trimers (136) and can activate TNF receptors. Moreover, the nucleus and transcription of TNF-␣ (1, 3, 156). In partic-
the intracellular domain of transmembrane TNF is palmitoy- ular, NFAT5 (also called Ton/EBP for tonicity element binding
lated (148) and can be phosphorylated (111), providing an protein) has been shown to partially mediate the CaSR-induced
additional step for regulation of TNF-␣ release. increase in TNF-␣ expression (53) and is itself activated by
Infiltrating inflammatory cells (142), podocytes (119), mes- changes in osmolality in renal cells (95); however, it is not
angial cells (6, 13, 14, 74), and epithelial cells from proximal known whether changes in osmolality induce TNF-␣ release by
tubules (101, 113, 163, 164), thick ascending limbs (3, 35, 90, thick ascending limbs nor whether this TNF-␣ release is
156) and collecting ducts (140) are sources of TNF-␣ in the mediated via NFAT5.
kidney. TNF-␣ increases in response to endotoxemia (26), TNF-␣ levels have been shown to increase in response to
lipopolysaccharide (LPS; Refs. 34, 40, 74, 90), angiotensin II ANG II in thick ascending limbs (35) and podocytes (119). In
(ANG II; Ref. 35), calcium-sensing receptor (CaSR) activation podocytes, activation of both AT1 and AT2 receptors was
(3, 156), hypertension (32, 79), renal failure (115), glomeru- responsible for this effect, with AT1 mediating the earlier
lonephritis (153), diabetic nephropathy (42, 100), and intersti- phase and AT2 the later phase. ANG II activates PKC in the
tial tubular nephritis (50, 94). thick ascending limb (57, 128) and thus may increase NFAT
translocation to the nucleus along with TNF-␣ gene transcrip-
Address for reprint requests and other correspondence: V. D. Ramseyer,
tion; however, it is still unclear whether PKC and NFAT
Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West mediate ANG II-induced increases in TNF-␣ expression in the
Grand Boulevard, Detroit, MI 48202-2689 (e-mail: vramsey1@hfhs.org). thick ascending limb. In addition, TNF-␣ production is known
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Review
F1232 TNF AND RENAL FUNCTION
to increase in response to LPS in thick ascending limbs and ANG II is elevated (under conditions like low-salt diet, renal
podocytes, particularly during endotoxemia. vascular hypertension, etc.), then receptor expression would be
Finally, TNF-␣ production in the kidney can be increased by elevated as well. Such data suggest that the cellular pattern of
infiltrating immune cells, especially macrophages (105, 142, TNFR expression in the kidney could affect its response to
169). Increased innate immune activation, neutrophil and mac- TNF-␣ depending on its initial physiological/pathophysiolog-
rophage infiltration, and enhanced TNF-␣ production are ob- ical state.
served in infections (83), cisplatin nephropathy (73, 114),
diabetic nephropaty (38), antiglomerular basement membrane TNF-␣ and Blood Pressure
nephropathy (142), obstructive nephropathy (134), etc. In such
situations stimuli for TNF-␣ production include activation of The role of TNF-␣ in blood pressure regulation has been
Toll-like receptor 4 in response to LPS (85), oxidative stress studied in several different models, with sometimes conflicting
(30), antibody deposition, and complement activation (142, results. There are a number of reports showing that TNF-␣
159). In addition, dendritic cell, macrophage, and lymphocyte either mediates or supports increases in blood pressure. In
recruitment to the kidney is observed in lupus erythematosus ANG II-infused hypertensive rats fed high-salt diet, etanercept
and hypertension (27, 51, 96). The stimuli for their migration delayed progression of hypertension. Protection appeared to be
to the kidney and TNF-␣ production are likely increased due to reduced renal damage, since proteinuria and monocyte/
reactive oxygen species and enhanced expression of endothe- macrophage infiltration were diminished (33). In addition,
lial adhesion molecules and chemokines by the kidney in infusion of ANG II for 2 wk failed to increase blood pressure
response to elevations in renal-derived TNF-␣. Inhibition of in TNF-␣ knockout (KO) mice, but this was restored by replace-
AT1 receptors (7, 121) as well as reactive oxygen scavenging ment therapy with recombinant TNF-␣ (0.3 g·kg⫺1·day⫺1; Ref.
(30) reduces renal-derived TNF-␣, proinflammatory cytokine 131). In addition, Guzik et al. (51) showed that TNF-␣ pro-
production, and immune cell infiltration and activation. Simi- duction by T lymphocytes from ANG II-hypertensive mice was
larly, ANG II infusion increases leukocyte infiltration and higher than in control mice and that etanercept infusion blunted
production of inflammatory cytokines, all of which are pre- ANG II-induced increases in blood pressure. These data seem
vented by blockade of TNF-␣ with etanercept (33, 96). These to indicate that TNF-␣ mediates ANG II-dependent increases
data indicate that endotoxins, ANG II, and reactive oxygen in blood pressure. Similarly, in a mouse model of lupus
species stimulate TNF-␣ expression by the kidney; this in turn erythematosus etanercept infusion for 4 wk reduced blood
induces inflammatory cell recruitment and activation, which pressure, albuminuria, glomerulosclerosis, and NF-B activity,
further increase TNF-␣ levels. suggesting that TNF-␣ causes inflammation and mediates the
increase in blood pressure (152).
TNF-␣ Receptors Metabolic syndrome is characterized by the simultaneous
presence of obesity, dyslipidemia, insulin resistance, and hy-
The actions of TNF-␣ are mediated by two distinct recep- pertension. It has been shown that elevated TNF-␣ levels are
tors: type 1 (TNFR1 or p55) and type 2 (TNFR2 or p75). associated with the development of hypertension (63, 170).
Kinetically, TNF-␣ binding to TNFR1 shows slow dissocia- Etanercept treatment for 6 wk prevented the increase in blood
tion, whereas it is 20 –30 times faster with TNFR2 (48). pressure observed in insulin-resistant fructose-fed rats without
Therefore, some have proposed that TNFR2 serves as a “local affecting insulin sensitivity (147). TNF-␣ neutralization also
reservoir” of TNF-␣, both providing readily available TNF-␣ restored maximum acetylcholine-induced relaxation in mesen-
for TNFR1 activation and operating as a “ligand passing” teric arteries and restored nitric oxide synthase 3 (NOS3)
receptor in which TNFR2 captures TNF-␣ and passes it on to expression (147).
TNFR1. In addition, it has been shown that TNFR1 activation TNF-␣ also appears to play a role in blood pressure regula-
requires expression of TNFR2, which can form heterocom- tion during pregnancy. In preeclampsia, plasma TNF-␣ is
plexes with TNFR1 (28, 87, 107). Although the effects of doubled (10, 25, 122), and infusing TNF-␣ for 5 days (⬍0.5
soluble TNF-␣ may be mediated by either receptor, most of the g·kg⫺1·day⫺1) increases blood pressure in pregnant rats but
actions of membrane-bound TNF-␣ are mediated by TNFR2 not in virgin rats (80, 81). Blockade of TNF-␣ with etanercept
(47). TNFRs form homotrimers in the plasma membrane via reduced blood pressure. In addition, healthy endothelial cells
their preligand assembly domain (22). TNFRs do not have an incubated with serum from preeclamptic rats exhibited in-
intrinsic catalytic property; rather, ligand binding causes a creased endothelin-1 release and this was prevented by etan-
conformational change in the preassembled receptor that leads ercept (79). Similarly, infusion of a neutralizing anti-TNF
to recruitment of signaling proteins. antibody reduced blood pressure, albuminuria, and renal dam-
In healthy animals, TNFR1 and 2 have been found in the age in a model of preeclampsia achieved by adoptive transfer
cortex in proximal tubules and collecting ducts as well as of serum from preeclamptic women to pregnant mice (62).
endothelial cells of the glomeruli and renal vasculature (8, 20). Finally, TNF-␣ is increased is chronic kidney disease, which
TNFR1 has also been found in vascular smooth muscle cells of is characterized by progressive loss of renal function, renal
the renal vasculature (20). However, TNFR expression varies injury, and hypertension (130, 139, 162). This disease can be
in different diseases. In glomerulonephritic kidneys, TNFR2 mimicked by 5/6 nephrectomy, which also increases TNF-␣
expression was high in glomeruli and postcapillary venules of release. In rats with renal failure, neutralizing TNF-␣ with
the cortex, whereas in obstructive nephropathy (which primar- soluble TNFR1 prevented the increase in blood pressure,
ily affects tubules) TNFR2 staining was restricted to tubular reduced fibrosis, decreased macrophage infiltration and albu-
epithelial cells (153). ANG II also increases TNFR1 and 2 minuria, and restored the ratio of L-arginine to asymmetric
expression in podocytes (119). Thus one would expect that if dimethylarginine (139). It also restored expression of NOS3,
↑ macrophage infiltration
tion rate (GFR), and urinary output were also increased
blood pressur
↑ neutrophile infiltration
whereas Na excretion was reduced, suggesting increased renal ↓ ↓ GFR
Na reabsorption. These results are in stark contrast to those ↓ ↓ RBF
p
shown in TNF-␣ KO mice (131) where the increase in blood ↑ macrophage infiltration ↓ proteinuria
pressure induced by infusion of 1 g·kg⫺1·min⫺1 ANG II was ↑ lymphocyte activation
↓ NOS3 and NO
Renal failure
(m
(12). In addition to reducing NKCC2, TNF-␣ reduces expres- but V2 receptor and aquaporin 2 expression were decreased,
sion of thick ascending limb K channels (126), which would whereas a siRNA against the TNFR p50 subunit attenuated the
also be expected to reduce Na absorption. Finally, TNF-␣ decrease in these proteins (58). Thus TNF-␣ may reduce
reduces NOS3 expression and NO production in this nephron vasopressin-dependent water retention due to both inhibition of
segment (116). NO produced in response to arginine (103, 110) water transport and reductions in the osmotic gradient developed
endothelin-1 (109, 56) and clonidine (108) reduces NaCl re- by the thick ascending limb, which drives water absorption.
absorption mainly by decreasing NKCC2 activity by the thick Maintenance of urinary osmolality depends not only on
ascending limb. These data suggest that TNF-␣ affects Na water and Na but also in large measure on urea. Blous infusion
transport regulation by the thick ascending limb by reducing of TNF-␣ at a dose of 1 mg/kg decreased fractional urea
basal Na reabsorption while blunting the ability of other excretion, inner medulla urea concentration and osmolality,
natriuretic autacoids and hormones to further decrease trans- tubular urea reabsorption, and urinary urea, whereas it
port. Given that thick ascending limbs absorb 30% of the increased plasma osmolality and urea. Such findings were
filtered Na load, it is likely that direct actions of TNF-␣ in this attributed to reduced urea transporters UTA1, UTA2, UT-A3,
segment contribute to elevated Na excretion (Fig. 2B). UT-A4, and UT-B (124).
In Madin-Darby canine kidney cells, a canine model of In addition to affecting Na and fluid absorption, TNF-␣ may
distal tubular cells, TNF-␣ increases paracellular permeability diminish glucose absorption in the proximal nephron. Injection
by activating RhoA GTPase, Rho kinase, and myosin light of TNF-␣ (1 mg/kg, bolus) decreases expression of sodium
chain kinase, similar to LLCPk1 cells (69, 70). The net effect glucose transporters SGLT2 and SGLT3 and Na-K-ATPase
of this activity on transport is unknown. within 12 h; however, it also increases Glut1 and SGLT1 in the
In mpkCCDcL4 cells, a murine collecting duct cell line, 10 kidney. The increase in Glut1 and SGLT1 may occur as a
ng/ml TNF-␣ increased protein kinase A (PKA) activity inde- compensatory response to the reduced intracellular glucose
pendently of cAMP. LPS and TNF-␣ both increased transep- levels resulting from 1) decreased glucose entry due to reduc-
ithelial Na transport, measured as an increase in amiloride-
tions in SGLT2 and 3, and 2) the lower Na gradient due to
sensitive short-circuit current, and this effect depended on
reduced Na-K-ATPase (125).
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; Renal Injury
however, this effect was only seen when phosphatidylinositol Even though inhibition of transport could be interpreted as
3-kinase (PI3K) was inhibited. TNF-␣ inhibited ENaC via a protecting the kidney from injury, the majority of the literature
mechanism that involved activation of sphingomyelinase and indicates that TNF-␣ induces renal damage. In part, this is
increased ceramide and activation of PKC, which in turn undoubtedly due to diminished renal perfusion such as seen in
induced externalization of phosphatidylserine. The presence of sepsis (84, 127). It is also due in part to recruitment of immune
phosphatidylserine in the cytosolic leaflet of the apical mem- cells into the kidney, releasing cytokines that cause inflamma-
brane is sufficient to maintain ENaC activity; thus disappear-
tion and cell death (169). Finally, it is also likely due to direct
ance of this phospholipid from the inner leaflet was likely the
actions of TNF-␣ on renal cells (65, 102).
cause of reduced ENaC activity (11). The role of PI3K in
TNFR1 contains a death domain, and thus the proapoptotic
preventing this effect was attributed to its ability to inhibit
actions of TNF-␣ have been mainly attributed to this receptor
sphingomyelinase activity (18). These disparate findings could
(138, 64). TNFR1 interacts with the adaptor protein TNF recep-
be explained by differences in the concentration of TNF-␣
tested, the experimental conditions, or the origin of the respec- tor-associated death domain (TRADD) through TNFR1-DD (59),
tive cells. For example, the A6 cells were grown with 1 g leading to recruitment of TNF receptor-associated factor 2
aldosterone whereas the mpkCCD cells were not, and aldoste- (TRAF2; Ref. 133). TRAF2 then interacts with the E3 ubiquitin
rone activates PI3K (55). Whether or not other pertinent ligases “cellular inhibitor of apoptosis” (c-IAP) 1 and 2 to form
hormones are also present in the collecting duct and ultimately the membrane-bound complex I (93). c-IAP polyubiquitinates
determine whether TNF-␣ increases or decreases ENaC activ- chains of RIP1, which is essential for recruitment of transforming
ity could be the key to understanding its opposing effects on growth factor-activated kinase 1 (TAK1) and activation of inhib-
tubular transport and blood pressure. When infused in vivo, itor of kappa B (IB) kinase (IK; Ref. 29). IK phosphorylates
TNF-␣ reduces expression of all three subunits of ENaC (126); IB, which is then degraded via the ubiquitin-proteasome path-
thus its actions on the cortical collecting duct likely also way, allowing NF-B to translocate to the nucleus where it
contribute to the natriuresis caused by systemic infusion (Fig. initiates gene transcription targeting anti-apoptotic genes like
2C). Finally, TNF-␣ increases nitrate/nitrite formation in inner c-FLIP, c-IAP-1 and 2, and TRAF1 and 2. Additionally, associ-
medullary collecting ducts, suggesting elevated NO production ation of RIP1 and TRAF-2 with TNFR1 can lead to activation of
that was supported by increased iNOS (68, 91) and NO has mitogen-activated protein kinase kinase kinase 1 (MEKKK-1)
been reported to inhibit Na reabsorption by this segment (132). and c-Jun NH2-terminal kinases (JNK), which phosphorylate and
TNF-␣ KO mice showed increased ambient urinary osmo- activate c-Jun, a member of the transcription factor complex
lality compared with WT, but water deprivation for 24 h activator protein 1. Prolonged JNK activation mediates protea-
increased urine osmolality to the same extent in both strains somal degradation of c-FLIP and activation of caspase-8, leading
(12). LPS, which potently induces TNF-␣ release, decreases to apoptosis (23, 135). TNF-␣ also activates apoptosis signaling
arginine-vasopressin type 2 receptor levels and aquaporin 2 kinase-1 (ASK1) via TNFR1 by inducing ASK1-interacting pro-
expression in the renal inner medulla (49). In support of this, in tein-1, which promotes ASK1 dissociation from the adaptor pro-
a model of sepsis plasma arginine vasopressin did not change tein 14 –3-3, phosphorylation at the stimulatory site threonine 845
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AUTHOR CONTRIBUTIONS
endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl
Author contributions: V.R. prepared figures; V.R. drafted manuscript; V.R. Acad Sci USA 72: 3666 –3670, 1975.
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