Knotek M, Rogachev B, Wang W, Ecder T, Melnikov V, Gengaro P E, Esson M, Edelstein C L, Dinarello C A, Schrier R W
Department of Medicine, Division of Renal Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Kidney Int. 2001 Jun;59(6):2243-9. doi: 10.1046/j.1523-1755.2001.00740.x.
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.
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).
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.
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.
肾衰竭是脓毒症常见的并发症，死亡率很高。肿瘤坏死因子（TNF）被认为是脓毒症或内毒素血症急性肾衰竭的一个因素。最近的研究还表明，诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）参与内毒素诱导的肾衰竭的发病机制。本研究检验了TNF在内毒素性肾衰竭中的作用是由iNOS衍生的NO介导的这一假说。
对内毒素血症（大肠杆菌脂多糖（LPS），5mg/kg腹腔注射）野生型和iNOS基因敲除小鼠的肾功能进行评估。通过TNF可溶性受体（TNFsRp55）评估TNF中和对内毒素血症小鼠肾功能的影响。
给野生型小鼠注射LPS后16小时，肾小球滤过率（GFR）下降70%，肾血浆流量（RPF）减少40%。这些结果与低血压、形态学改变、细胞凋亡和白细胞聚集无关。在用TNFsRp55预处理的小鼠中，与用载体处理的小鼠相比，对LPS的反应仅观察到GFR下降30%，而RPF无显著变化。此外，与未处理的内毒素血症野生型小鼠相比，用TNFsRp55预处理的内毒素血症野生型小鼠血清NO浓度显著降低（260±52对673±112μmol/L，P<0.01）。在注射LPS的iNOS基因敲除小鼠和用选择性iNOS抑制剂1400W处理的野生型小鼠中，肾衰竭的发展与野生型小鼠相似。与野生型小鼠一样，在给予LPS的iNOS基因敲除小鼠中，TNFsRp55显著减轻了GFR的下降（下降33%，而无TNFsRp55时为75%），而RPF无显著变化。
这些结果表明，在脓毒症小鼠模型中，TNF在早期肾功能障碍（16小时）中起作用，与iNOS、低血压、细胞凋亡、白细胞聚集和形态学改变无关，因此提示肾血管收缩剂和血管舒张剂之间失衡继发的肾灌注不足，而这种失衡尚未明确。
