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* Section of Nephrology, Department of Medicine, and
Section of Transplantation Surgery, University of Chicago, Chicago, IL 60637
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sepsis is a leading cause of acute renal failure (ARF)3 (11, 12, 13), but the mechanisms behind this ARF remain unclear. Although cytokines such as TNF are key mediators of sepsis, little is known about their acute effects on the kidney in the setting of endotoxemia. We previously observed that, despite severe impairment of kidney function following LPS administration, the extent of renal pathologic injury is mild (14). To explain this dissociation between the severe functional impairment, yet the relatively mild pathologic injury seen in LPS-induced ARF, we hypothesized that apoptosis, which is difficult to detect by routine histologic studies, is responsible for renal cellular dysfunction and death. Of note, TNF has been shown to induce apoptosis in a variety of cell types, including renal tubular cells (15, 16). Therefore, we investigated the role and mechanisms of action of TNF in endotoxin-induced ARF.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice with a mutation in the Fas gene (B6.MRL-Faslpr; denoted Fas-/-) or with targeted deletion of TNFR1 (TNFR1-/-) or TNFR2 (TNFR2-/-) were obtained from The Jackson Laboratory (Bar Harbor, ME) and used for experiments at 8 wk of age. Because each of these genotypes is on a C57BL/6 background, age-matched C57BL/6 mice were used as controls. The animals were maintained and experiments were performed in accordance with the guidelines set by the University of Chicago Institutional Animal Care and Use Committee.
ARF model
Under isoflurane inhalational anesthesia, mice were given 0.15 mg Escherichia coli LPS (Sigma-Aldrich, St. Louis, MO) as an i.p. injection. Blood was obtained via retro-orbital bleeding immediately before injection and 24 h later, with sacrifice and harvest of kidney tissue and blood at 48 h after injection. Portions of kidney tissue were frozen in OCT compound (Fisher Scientific, Pittsburgh, PA) at -80°C, and also formalin-fixed and stained with periodic acid-Schiff base and H&E. Blood urea nitrogen (BUN) concentrations were determined with a Beckman CX5CE autoanalyzer (Beckman, Palo Alto, CA). At this relatively low dose of LPS, systemic blood pressure falls by <10 mm Hg in C57BL/6 mice (Ref. 17 and our unpublished observations). To evaluate the possibility that TNFR2-/- mice had an enhanced susceptibility to LPS-induced ARF, TNFR2-/- mice and their control group were given LPS at a lower dose of 0.075 mg, the rationale for which is described in greater detail below.
TUNEL staining
Mice were sacrificed at varying times after i.p. injection of 0.15 mg LPS, and kidney tissue was immediately frozen in OCT compound. TUNEL staining was performed with the TdT-FragEL DNA fragmentation detection kit (Oncogene, Boston, MA) according to the manufacturer’s instructions. In brief, 8-µm cryostat sections were washed in Tween 20/TBS and fixed in 4% formaldehyde for 30 min. This was followed by proteinase K treatment for 18 min and incubation in 3% H2O2/methanol for 7 min. Specimens were incubated with TdT at 37°C for 60 min, blocked in dilute BSA for 20 min, and incubated in streptavidin-HRP for 30 min, followed by detection with diaminobenzidine reagent for 15 min. Sections were counterstained with methyl green, and a blinded observer counted the number of positively stained nuclei per high-power field and recorded the average of 10 fields for each sample.
LM-PCR
Kidney tissue was harvested at various time points after injection of 0.15 mg LPS and immediately frozen at -80°C. Later, a small piece was thawed, from which DNA was purified (DNeasy DNA purification system; Qiagen, Valencia, CA). The extent of DNA laddering was amplified and detected by ligase-mediated (LM)-PCR (Clontech Laboratories, Palo Alto, CA) according to the manufacturer’s instructions, as follows. DNA isolated from each animal was incubated with the supplied primer targets and T4 DNA ligase for 18 h at 16°C. Twenty micrograms of this ligated DNA was then used as the substrate for PCR, using supplied primers and Advantage DNA polymerase (Clontech Laboratories) for 23 cycles of 94°C for 1 min and at 72°C for 3 min. The reaction product for each animal was run on a 1.3% agarose gel, and ethidium bromide-stained bands were detected with UV light illumination.
Kidney transplantation
A single kidney was transplanted from 10-wk-old TNFR1-/- to TNFR1+/+ mice, and vice versa. Each individual mouse was used only as a recipient or a donor. Mice were anesthetized with 65 mg/kg pentobarbital i.p. The left kidney of donor mice was perfused via the renal artery with 0.3 ml cold saline and resected with artery, vein, and ureter attached. The kidney was stored at 4°C until anastomosis. Next, the recipient underwent midline abdominal incision, followed by suprarenal clamping of aorta and inferior vena cava. The donor kidney was placed in the right flank, and its artery and vein were attached with 10-0 nylon suture via side-to-end anastomoses with the recipient aorta and inferior vena cava. The bladder was punctured with a 21-gauge needle, and the ureter was sewn in place. Native kidneys were then resected. Animals were allowed to recover for 10 days after surgery before LPS injection. Preliminary dosing experiments using syngeneic C57BL/6 kidney transplants showed that mouse kidney transplant recipients have a stable, mild elevation of BUN and creatinine but are somewhat more sensitive to LPS; thus, a dose of 0.1 mg was used in these studies.
Tissue processing
Histologic sections for each animal were assigned a semiquantitative score for tubular injury adopted from Nomura et al. (18). A blinded observer assigned a score ranging from 0 (no injury) to 3 (severe/widespread injury) for each of three variables: tubular dilatation/flattening, tubular casts, and tubular degeneration/vacuolization. For each animal, 10 cortical and 10 medullary high-power fields were examined at random. For each variable within each field a score of 0 was assigned when <5% of the tubules were affected, a score of 1 when 5–33% were affected, a score of 2 when 34–66% were affected, and a score of 3 when >66% were affected. The average score for each variable was calculated separately for the cortex and medulla, and all three variables from both cortex and medulla were summed to arrive at a total injury score for each animal ranging from 0 to 18.
For immunohistochemistry, 4-µm kidney cryostat sections were fixed with ether/ethanol, incubated with 0.3% H2O2 for 30 min, and blocked with dilute horse serum. Sections were stained for neutrophils by sequential incubation with rat anti-mouse neutrophil (mAb 7/4; Serotec, Raleigh, NC) at a 1/60 dilution for 30 min followed by HRP-conjugated rabbit anti-rat IgG (Sigma-Aldrich) at a 1/60 dilution for 30 min and diaminobenzidine reagent (Vector Laboratories, Burlingame, CA) for 10 min. A blinded observer counted the number of neutrophils per high-power field and recorded the average of 10 fields for each sample. Sections were stained for TNFR1 by incubation with hamster anti-mouse TNFR1 (BD PharMingen, San Diego, CA) at a 1/60 dilution for 30 min, followed by biotin-conjugated mouse anti-hamster IgG (BD PharMingen) at a 1/100 dilution for 30 min, streptavidin-HRP (Vector Laboratories) for 30 min, and diaminobenzidine reagent.
Measurement of TNF release
In a parallel set of experiments, blood was collected from wild-type C57BL/6 mice (n = 8) at baseline and again 2 h after LPS injection. Serum was analyzed for TNF levels using a commercially available TNF ELISA kit (R&D Systems, Minneapolis, MN) according to the manufacturer’s instructions.
mRNA transcript profiling in LPS-injected mice
For microarray studies, normal C57BL/6 mice were given 0.15 mg LPS, and 4 or 8 h later tissue was harvested and kidney RNA was isolated using TRIzol reagent (Life Technologies, Grand Island, NY). RNA from the kidney of a mouse injected with saline served as the control. RNA was processed and hybridized with murine genome U74A arrays (Affymetrix, Santa Clara, CA) according to the manufacturer’s instructions.
Real-time RT-PCR for inducible NO synthase (iNOS) was performed as follows. A portion of whole kidney from each TNFR1-/- and TNFR1+/+ mouse was frozen at -80°C, from which total RNA was purified using the RNeasy Mini RNA purification kit (Qiagen). To remove all traces of genomic DNA, samples were then treated with RNase-free RQ1 DNase (1 U per 4 µg RNA; Promega, Madison, WI) in 10 µl reaction buffer (final concentration, 40 mM Tris-HCl, 10 mM MgSO4, and 1 mM CaCl2 (pH 8)) at 37°C for 30 min. This was followed by addition of 1 µl 20 mM EGTA (pH 8) to stop the reaction and incubation at 65°C for 10 min to inactivate the DNase. cDNA was generated from RNA using random hexamers as primers with the SuperScript first-strand synthesis kit (Life Technologies), according to the manufacturer’s instructions. cDNA was prepared in an analogous fashion from kidneys of mice sacrificed 6 h after LPS injection and compared with sham-injected kidney cDNA for analysis of early TNF and TNFR1 mRNA (n = 6 per group).
Real-time PCR was performed using a Smart Cycler (Cepheid, Sunnyvale,
CA). For iNOS and GAPDH measurements, probes were labeled at the 5' end
with the reporter dye molecule FAM (6-carboxyfluorescein; emission
max = 518 nm) and at the 3' end with the
quencher dye molecule TAMRA (6-carboxytetramethyl-rhodamine; emission
max = 582 nm). Each reaction was conducted in
a total volume of 25 µl with 1x TaqMan Master Mix (PE Applied
Biosystems, Foster City, CA), 3 µl sample or standard cDNA, primers
at 200 nM each, and probe at 100 nM. PCR was conducted with a hot start
at 95°C (5 min), followed by 45 cycles of 95°C for 15 s and
60°C for 30 s. For each sample, the number of cycles required to
generate a given threshold signal (Ct)
was recorded. Using a standard curve generated from serial dilutions of
splenic cDNA, the ratio of iNOS expression relative to GAPDH expression
was calculated for each experimental animal and normalized relative to
an average of ratios from TNFR1+/+ kidney
unexposed to LPS (n = 5). Measurements of TNF and TNFR1
mRNA expression relative to GAPDH were performed in an analogous
fashion, but using the SybrGreen intercalating dye method with HotStar
DNA polymerase (PE Applied Biosystems) instead of labeled probes.
Reaction conditions were according to the manufacturer’s instructions.
The reaction temperature profiles for TNF and TNFR1 were as described
above, except that the annealing temperature was 58°C. Primers were
synthesized by Integrated DNA Technologies (Coralville, IA) and probes
by Synthegen (Houston, TX). The sequences of primers/probes were as
follows: iNOS forward primer, 5'-CAGCTGGGCTGTACAAACCTT-3'; iNOS reverse
primer, 5'-TGAATGTGATGTTTGCTTCGG-3'; iNOS probe,
5'-CGGGCAGCCTGTGAGACCTTTGA-3'; GAPDH forward primer,
5'-GGCAAATTCAACGGCACAGT-3'; GAPDH reverse primer,
5'-AGATGGTGATGGGCTTCCC-3'; GAPDH probe,
5'-AAGGCCGAGAATGGGAAGCTTGTCATC-3'; TNF forward primer,
5'-CCGATGGGTTGTACCTTGTC-3'; TNF reverse primer,
5'-GTGGGTGAGGAGCACGTAGT-3'; TNFR1 forward primer,
5'-GACCGGGAGAAGAGGGATAG-3'; and TNFR1 reverse primer,
5'-GTTCCTTTGTGGCACTTGGT-3'.
Statistics
Data were analyzed with Minitab software (State College, PA).
Unless noted otherwise, data are given as the mean ± SEM. Groups
were compared by two-sample t test. When comparing the
severity of ARF between two groups, the slope of BUN vs time was
determined for each individual animal by least squares regression, and
the individual slopes in the two groups were compared with the
Mann-Whitney rank-sum test. A value of p 
0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several factors present in sepsis can serve as triggers of apoptosis, including hypoxia and reactive oxygen species (19, 20). Additionally, apoptosis can be induced in a variety of cell types, including renal tubular cells, in a receptor-mediated fashion, via Fas, TNFR1, and other TNFR family members (15, 16, 20, 21, 22, 23). To examine whether apoptosis occurs in the kidney after LPS administration, TUNEL staining was performed on kidney sections following administration of LPS to mice.
Normal mice had few TUNEL-stained nuclei, while LPS administration led
to an increase in the number of apoptotic cells at time points ranging
from 3 to 48 h later (0.8 ± 0.2 vs 2.3 ± 0.3
TUNEL-stained nuclei per high-power field at 8 h;
p = 0.022; Fig. 1
). Most
apoptotic cells appeared to be tubular epithelial cells. To further
quantify the extent of apoptosis, LM-PCR was performed to amplify
fragmented DNA from kidney specimens. This demonstrated that the
limited extent of apoptosis present in normal kidney was increased in a
time-dependent fashion following LPS administration (Fig. 2).
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In addition to the release of TNF into the circulation that occurs
after LPS administration, Fas and Fas ligand have been shown to be
up-regulated on the surface of renal tubular cells following LPS
administration in vivo (24). Thus, we hypothesized that
one or both of these pathways could account for renal cell apoptosis
and ARF following LPS administration. Fas-/-
mice developed ARF to the same extent as Fas+/+
controls following LPS injection (Fig. 3A). In contrast,
TNFR1-/- mice were resistant to LPS-induced ARF
(Fig. 3B; n = 8 per group; p
= 0.005 compared with TNFR1+/+ mice). In addition
to protection from renal functional impairment,
TNFR1-/- mice had less renal tubular injury
(tubular injury scores of 3.9 ± 0.6 vs 7.1 ± 1.1 in
TNFR1-/- and TNFR1+/+
mice, respectively; p = 0.027; Fig. 4). Therefore, TNF, acting through TNFR1,
is a key mediator of LPS-induced ARF. Renal apoptosis, as assessed by
LM-PCR, was greater in the TNFR1+/+ controls than
in the TNFR1-/- group. Furthermore, the amount
of apoptosis in individual animals correlated with the extent of renal
functional impairment (Fig. 5),
suggesting that apoptosis is intimately involved in LPS-induced
ARF.
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C) and tubular injury scores (5.6 ± 0.3 vs
5.3 ± 0.3 in TNFR2-/- and
TNFR2+/+ mice, respectively; p =
0.42). By LM-PCR, TNFR2-/- and
TNFR2+/+ mice had a similar amount of apoptosis
in the kidney after LPS administration (data not shown). Therefore,
TNFR2 does not appear to have a role in mediating the ARF or renal
apoptosis induced by LPS. TNFR1 mediates LPS-induced neutrophil infiltration in the kidney
In addition to apoptosis, there are other mechanisms by which
TNFR1 could mediate LPS-induced renal injury. Although relatively mild,
the pathologic changes seen in TNFR1+/+ mice
after LPS administration cannot be explained by the noninflammatory
process of apoptosis. TNF has been shown to stimulate the oxidative
burst of neutrophils (28, 29, 30) and to up-regulate the
expression of chemokines (31) and adhesion molecules
(32, 33, 34) that mediate neutrophil recruitment to tissues
following an inflammatory stimulus. Neutrophils have been implicated in
the pathogenesis of LPS-induced injury of the liver and lung
(35, 36, 37) and in ischemia-reperfusion injury of the kidney
(38, 39). We confirmed that neutrophils infiltrated the
kidney following LPS administration, but to a significantly lesser
extent in TNFR1-/- mice compared with
TNFR1+/+ controls (5.4 ± 0.8 vs 9.0 ±
1.3 neutrophils per high-power field in
TNFR1-/- and TNFR1+/+
mice, respectively; p = 0.039; Fig. 6). Additionally, the extent of renal
neutrophil accumulation correlated with the degree of renal functional
impairment in individual animals, as measured by BUN levels
(r = 0.89; p < 0.001), further
supporting a role for TNF-mediated neutrophil recruitment in the
pathogenesis of LPS-induced ARF.
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NO is a key mediator of a wide range of inflammatory as well as
anti-inflammatory processes and has been shown to have direct
cytotoxic effects on renal tubular cells (40) as well as
complex actions on the renal vasculature (41). Inducible
NOS has been shown to be strongly up-regulated in a wide variety of
tissues, including the kidney, after administration of LPS
(42). By real-time RT-PCR, expression of iNOS mRNA in the
kidney was markedly up-regulated in both
TNFR1-/- and TNFR1+/+
mice given LPS compared with the baseline value, but with no
statistical differences between the two groups (4.7 ± 1.3- and
8.7 ± 3.0-fold increases in TNFR1-/- and
TNFR1+/+ mice, respectively; p =
0.25; Fig. 7). Furthermore, iNOS
expression did not correlate with BUN levels (r =
0.326; p = 0.24). Thus, despite induction of iNOS mRNA
as in wild-type controls, TNFR1-/- mice are
protected from LPS-induced ARF.
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As has been documented by others, the injection of LPS led to profound release of TNF into the circulation within 2 h (0.02 ± 0.02 ng/ml at baseline vs 2.70 ± 0.65 ng/ml 2 h after LPS; p < 0.001). The release of TNF soon after LPS administration is responsible for the later appearance of other circulating cytokines (43, 44). Also, injection of TNF in vivo duplicates the severe hypotension seen in septic shock (45). Thus, TNF could mediate LPS-induced ARF indirectly, by inducing systemic hypotension and/or by leading to the release of other inflammatory mediators into the circulation that could act on the kidney. Alternatively, LPS-induced ARF could be mediated by TNF acting directly on renal TNFR1. In support of the latter possibility, kidney sections from normal C57BL/6 mouse kidney stained positively for TNFR1, predominantly in cortical tubules (data not shown). In addition, using a microarray approach, we found TNFR1 mRNA to be up-regulated in the kidney by factors of 2.3- and 5.9-fold at 4 and 8 h after LPS administration, respectively. These preliminary data were confirmed in subsequent experiments using real-time RT-PCR, showing that TNFR1 mRNA was up-regulated 3.0 ± 0.2-fold in kidney at 6 h after LPS administration in comparison with sham-injected controls (n = 6 per group; p < 0.001).
To address the question of the level of action of TNF, we transplanted
kidneys between TNFR1+/+ and
TNFR1-/- mice and examined their responses to
LPS. TNFR1+/+ kidneys in
TNFR1-/- mice developed severe ARF after LPS
administration, which was not the case for
TNFR1-/- kidneys in
TNFR1+/+ recipients (n = 4 per
group; p = 0.029; Fig. 8). As with native kidneys in
TNFR1-/- mice, pathologic specimens of
transplanted TNFR1-/- kidneys had less injury
than transplanted TNFR1+/+ kidneys (tubular
injury scores of 3.6 ± 0.6 vs 5.8 ± 0.4; p
= 0.062). These data prove that TNF causes LPS-induced ARF through its
action on TNFR1 in the kidney. In addition to its systemic release, TNF
was also strongly up-regulated in the kidney (14.6 ± 3.5-fold
increase 6 h after LPS injection; n = 6;
p < 0.001) as assessed by real time RT-PCR, suggesting
that not only systemic but also locally produced TNF was acting through
TNFR1 to cause LPS-induced ARF, as has been previously suggested
(46). TNFR1-/- transplanted
kidneys had significantly less neutrophil accumulation (3.9 ± 1.4
vs 12.0 ± 0.7 PMNs/high-power field in
TNFR1-/- and TNFR+/+
kidneys, respectively; p = 0.015) as well as a lesser
extent of apoptosis as quantified by LM-PCR (data not shown), further
strengthening a role for both apoptosis and neutrophil-mediated injury
in the pathogenesis of LPS-induced ARF.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The multisystem organ failure that occurs in sepsis is often ascribed to widespread hypotension and impairment of oxygen delivery. This explanation is especially intuitive in the kidney, where hemodynamic forces drive glomerular filtration, and a high metabolic activity exists in the transporting tubular epithelium (47, 48). TNF is well known to lead to the release of multiple other cytokines into the circulation (43, 44). Thus, we posed the question of whether TNF mediates LPS-induced ARF indirectly, by leading to hypotension and/or the release of other inflammatory mediators into the circulation. However, our data showing severe LPS-induced ARF in TNFR1+/+ kidneys transplanted into TNFR1-/- recipients, with relative protection of TNFR1-/- kidneys in TNFR1+/+ recipients, prove that TNF mediates LPS-induced ARF directly in the kidney. In addition, the fact that TNFR1-/- mice are fully sensitive to LPS-induced mortality (9, 10) yet resistant to LPS-induced ARF further supports a renal-specific role for TNF.
A leading experimental model of ARF is that of ischemia-reperfusion, in which the renal artery is completely occluded for a period of time and then released. However, this is not an accurate simulation of what occurs in most cases of human ARF. Instead, sepsis with attendant multisystem organ failure is a leading cause of human ARF in most series (11, 12). Most pathologic specimens from human ARF show the same relatively mild degree of histologic damage that we note in our model (49, 50). Therefore, the conclusions we present here are especially relevant to ARF in humans.
Given the complexity of sepsis, the pathogenesis of LPS-induced ARF is probably multifactorial. Our studies point to two possible mechanisms by which TNF causes ARF: renal cell apoptosis and neutrophil infiltration. Apoptosis is increasingly recognized to play a key role in ischemia-reperfusion injury in the kidney and other organs (21, 51), and inhibition of apoptosis with caspase inhibitors has been shown to protect against ischemia-reperfusion renal injury (52). Overall, given our findings and the fact that TNF acting on TNFR1 is a well-described trigger of apoptosis (15, 16), it seems likely that in the setting of LPS-induced TNF release (3, 4), renal TNFR1 is activated and results in apoptosis. However, other known triggers of apoptosis, such as hypoxia or reactive oxygen intermediates, the latter perhaps derived from infiltrating neutrophils, which are present in the setting of sepsis could be relevant as well. Further delineation of the precise apoptotic pathways involved in LPS-induced ARF is the subject of ongoing work. A role for neutrophils in LPS- and ischemia-reperfusion-induced ARF has also been suggested by others (29, 38, 39). Our findings that TNFR1-/- mice given LPS were protected from ARF and had fewer neutrophils infiltrating the kidney are consistent with these previous observations. Possible mechanisms for the recruitment of neutrophils to the kidney include TNF acting through TNFR1 to up-regulate adhesion molecules such as E- and P-selectin and ICAM-1 (32, 33, 34) or chemotactic molecules such as IFN-inducible protein-10 and macrophage inflammatory protein-2 (31). The fact that apoptosis and neutrophil accumulation each correlated with the degree of LPS-induced renal failure in individual animals supports a causative role, but additional experiments must be conducted to determine the extent to which these mechanisms individually contribute to LPS-induced ARF and the extent to which these processes are interrelated.
NO has received great attention as an important mediator in ARF. Its role is complex, with both noxious and protective effects (53). Specific inhibition of iNOS, which is markedly up-regulated in the kidney after LPS administration, but not broad-spectrum NOS inhibition, has been shown to be protective against LPS-induced ARF, implying that it is the inducible isoform of NO synthase that mediates injury in this disease model (41). Because TNF has been shown to up-regulate iNOS in a variety of cell types, including rat proximal tubule cells (54), we hypothesized that the TNFR1-/- mice were resistant to LPS-induced ARF in part because of a lesser induction of iNOS. However, our finding that iNOS was up-regulated to a similar extent in both TNFR1-/- and TNFR1+/+ kidneys shows that signaling through TNFR1 is not required for iNOS transcription and that the resistance to LPS-induced ARF which we observed in TNFR1-/- mice must be due to other mechanisms. This finding that iNOS has little role in LPS-induced ARF in mice is in agreement with the observations of Knotek et al. (17) that iNOS-/- mice are still susceptible to LPS-induced ARF.
Clinical sepsis is a complex phenomenon, due to a variety of bacterial products released intermittently or continuously, often in the setting of considerable comorbidities, and is therefore imperfectly simulated by animal models. Nevertheless, the key role of bacterial endotoxin in severe sepsis is undisputed. Although human trials of TNF-blocking agents in septic shock have been disappointing because they do not appear to affect mortality (8), prevention of renal failure in septic patients receiving anti-TNF Ab has been observed (55). Taken together, these data in humans and mice are consistent and illustrate the predominant role of TNF in the ARF of sepsis. Further definition of the effects of TNF on the kidney will lead to a better understanding of the pathophysiology of ARF occurring during the course of sepsis.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Patrick N. Cunningham, Section of Nephrology, MC5100, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail address: pcunning{at}medicine.bsd.uchicago.edu
3 Abbreviations used in this paper: ARF, acute renal failure; BUN, blood urea nitrogen; iNOS, inducible NO synthase; LM, ligase-mediated.
Received for publication November 9, 2001. Accepted for publication March 6, 2002.
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G. Ramesh, S. R. Kimball, L. S. Jefferson, and W. B. Reeves Endotoxin and cisplatin synergistically stimulate TNF-{alpha} production by renal epithelial cells Am J Physiol Renal Physiol, February 1, 2007; 292(2): F812 - F819. [Abstract] [Full Text] [PDF]
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L. Wu, M. M. Tiwari, K. J. Messer, J. H. Holthoff, N. Gokden, R. W. Brock, and P. R. Mayeux Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice Am J Physiol Renal Physiol, January 1, 2007; 292(1): F261 - F268. [Abstract] |
TNFR1-/-; n =
4) developed marked ARF after injection of LPS. In contrast,
TNFR1-/- kidneys in TNFR1+/+ mice
(TNFR1-/-