Endotoxemic renal failure in mice: Role of tumor necrosis factor independent of inducible nitric oxide synthase

Endotoxemic renal failure in mice: Role of tumor necrosis factor independent of inducible nitric oxide synthase. 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 wile-type mice (260 ± 52 vs. 673 ± 112 μmol/L, P 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.