title: Endotoxemic renal failure in mice: Role of tumor necrosis factor independent of inducible nitric oxide synthase.
abstract: BACKGROUND
  Renal failure is a frequent complication of sepsis with a high mortality. Tumor necrosis factor (TNF) has been suggested to be a factor in the acute renal failure in sepsis or endotoxemia. Recent studies also suggest involvement of nitric oxide (NO), generated by inducible NO synthase (iNOS), in the pathogenesis of endotoxin-induced renal failure. The present study tested the hypothesis that the role of TNF in endotoxic renal failure is mediated by iNOS-derived NO.
  
  
  METHODS
  Renal function was evaluated in endotoxemic [Escherichia coli lipopolysaccharide (LPS), 5 mg/kg IP] wild-type and iNOS knockout mice. The effect of TNF neutralization on renal function during endotoxemia in mice was assessed by a TNF-soluble receptor (TNFsRp55).
  
  
  RESULTS
  An injection of LPS to wild-type mice resulted in a 70% decrease in glomerular filtration rate (GFR) and in a 40% reduction in renal plasma flow (RPF) 16 hours after the injection. The results occurred independent of hypotension, morphological changes, apoptosis, and leukocyte accumulation. In mice pretreated with TNFsRp55, only a 30% decrease in GFR without a significant change in RPF in response to LPS, as compared with vehicle-treated mice, was observed. Also, the serum NO concentration was significantly lower in endotoxemic wild-type mice pretreated with TNFsRp55, as compared with untreated endotoxemic wild-type mice (260 +/- 52 vs. 673 +/- 112 micromol/L, P < 0.01). In LPS-injected iNOS knockout mice and wild-type mice treated with a selective iNOS inhibitor, 1400W, the development of renal failure was similar to that in wild-type mice. As in wild-type mice, TNFsRp55 significantly attenuated the decrease in GFR (a 33% decline, as compared with 75% without TNFsRp55) without a significant change in RPF in iNOS knockout mice given LPS.
  
  
  CONCLUSIONS
  These results demonstrate a role of TNF in the early renal dysfunction (16 h) in a septic mouse model independent of iNOS, hypotension, apoptosis, leukocyte accumulation, and morphological alterations, thus suggesting renal hypoperfusion secondary to an imbalance between, as yet to be defined, renal vasoconstrictors and vasodilators.
authors.affiliation: Department of Medicine, Division of Renal Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: M
authors.initials: M
authors.lastname: Knotek
authors.forename: B
authors.initials: B
authors.lastname: Rogachev
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Ecder
authors.forename: V
authors.initials: V
authors.lastname: Melnikov
authors.forename: P E
authors.initials: PE
authors.lastname: Gengaro
authors.forename: M
authors.initials: M
authors.lastname: Esson
authors.forename: C L
authors.initials: CL
authors.lastname: Edelstein
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: R W
authors.initials: RW
authors.lastname: Schrier
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology; D017209:Apoptosis; D001794:Blood Pressure; D019446:Endotoxemia / Q000150:complications*; D005919:Glomerular Filtration Rate; D006977:Hypertension, Renal / Q000209:etiology / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000201:enzymology; D007962:Leukocytes; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D015703:Antigens, CD; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse