Mark Lisa A, Robinson Ann V, Schulak James A
Department of Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
J Surg Res. 2005 Dec;129(2):236-41. doi: 10.1016/j.jss.2005.06.019. Epub 2005 Sep 2.
The role of nitric oxide (NO) production because of inducible nitric oxide synthase (iNOS) in the pathogenesis of renal ischemia/reperfusion (I/R) injury is unclear. In this study the roles of both iNOS and NO were characterized in a rat model of renal I/R injury. In addition, the effect of iNOS inhibition on renal function was evaluated.
Sprague-Dawley rats underwent 45 min of left renal ischemia and contralateral nephrectomy followed by various periods of reperfusion and renal function analysis [plasma creatinine, fractional excretion of sodium (FENa), creatinine clearance (CrCl), and measurement of plasma and urine NO levels]. In addition, the effect of treatment with 1400W, a highly selective iNOS inhibitor, was evaluated.
Renal dysfunction peaked at 48 h after reperfusion and immunohistochemistry studies revealed iNOS expression in the vasculature (3 h) and renal tubules (48 h) after reperfusion. Renal function improved significantly in treated animals compared to controls [creatinine of 1.1 v. 1.9 mg/dl (P < 0.05) and CrCl of 0.54 v. 0.31 ml/min (P < 0.05), respectively]. In addition, FENa was decreased by 50%, plasma NO levels were significantly lower (32.7 v. 45.7 micromol/L, P < 0.01), and deposition of nitrotyosine in the tubules of treated rats was less than in control animals.
These data support the hypothesis that iNOS and NO are involved in the pathogenesis of renal I/R injury and suggests that use of iNOS inhibitors may be a valuable therapeutic strategy clinical situations where renal I/R may be prevalent.
诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）在肾缺血/再灌注（I/R）损伤发病机制中的作用尚不清楚。本研究在大鼠肾I/R损伤模型中对iNOS和NO的作用进行了表征。此外，评估了iNOS抑制对肾功能的影响。
将Sprague-Dawley大鼠进行45分钟的左肾缺血和对侧肾切除术，随后进行不同时间段的再灌注和肾功能分析[血浆肌酐、钠分数排泄（FENa）、肌酐清除率（CrCl）以及血浆和尿液NO水平的测量]。此外，评估了高选择性iNOS抑制剂1400W治疗的效果。
肾功能障碍在再灌注后48小时达到峰值，免疫组织化学研究显示再灌注后3小时血管系统和48小时肾小管中有iNOS表达。与对照组相比，治疗组动物的肾功能显著改善[肌酐分别为1.1 vs. 1.9 mg/dl（P < 0.05），CrCl分别为0.54 vs. 0.31 ml/min（P < 0.05）]。此外，FENa降低了50%，血浆NO水平显著降低（32.7 vs. 45.7 μmol/L，P < 0.01），治疗组大鼠肾小管中硝基酪氨酸的沉积少于对照组动物。
这些数据支持iNOS和NO参与肾I/R损伤发病机制的假说，并表明在肾I/R可能普遍存在的临床情况下，使用iNOS抑制剂可能是一种有价值的治疗策略。
