替米沙坦对5／6肾切除肾衰竭大鼠的肾脏保护作用及其机制研究

The renal protective effect of telmisartan on 5/6 nephrectomy rats with renal failure

目的探讨血管紧张素AT1受体拮抗剂替米沙坦对5／6肾切除肾衰大鼠的肾脏保护作用及可能作用机制。方法选用180～200g雄性SD大鼠30只建立5／6肾切除肾衰模型，分为假手术组、模型组和替米沙坦组，各10只。第12周时采用断头法处死大鼠，并检测各组大鼠血清尿素氮、肌酐及24h尿蛋白水平；取残余肾组织行病理检查，判断肾小球硬化、肾小管间质损伤程度；利用反转录聚合酶链反应（RT—PCR）和Western Blot检测过氧化物酶增殖体活化受体γ（PPARγ）和神经型一氧化氮合酶（nNOS）蛋白和mRNA的表达水平。结果3组肌酐、血清尿素氮及24h尿蛋白情况：假手术组：（35±4）μmol／L，（6．6±1．0）mmol／L，（30±4）mg／d；模型组：（91±10）μmol／L，（23．0±3．4）mmol／L，（96±21）mg／d；替米沙坦组（62±10）μmol／L，（15．3±1．3）mmol／L，（45±17）mg／d；与假手术组相比，模型组和替米沙坦组大鼠上述指标均明显升高（P〈0．01）；但与模型组相比，替米沙坦组各指标则明显降低（P〈0．05）。病理学检查示模型组大鼠肾组织有明显的肾小球硬化及肾小管间质损伤，肾小球硬化指数及肾小管间质损伤指数均较假手术组明显增高（P〈0．01）；而替米沙坦组上述指标则较模型组明显降低（P〈0．05）。Western Blot和RT—PCR显示模型组PPARγ、nNOS蛋白和mRNA的表达较假手术组明显下降（P〈0．05），而替米沙坦组PPAR3,和nNOS的表达则较模型组明显升高（P〈0．05）。结论大鼠5／6肾切除后，给予替米沙坦可以明显减轻肾小球硬化和肾间质纤维化的程度，其作用机制可能与其上调PPARγ和nNOS基因的表达有关，且二者有明显的相关性。

Objective To investigate the renal protective effect and possible mechanism of Angiotensin II AT1 Receptor antagonist telmisartan on 5/6 nephrectomy rats with renal failure. Methods Sprague Dawley SD male rats were randomly divided into sham-operation group, model group and telmisartan group. The 12th week rats were killed with decapitation method and serum urea nitrogen, creatinine and 24 h urinary protein were detected. Residual kidney tissue was taken for pathological examination to determine glomerular sclerosis and tubulointerstitial injury. Reverse transcription polymerase chain reaction （RT-PCR） and Western Blot were used to detect the expression of peroxisome proliferator-activated receptor-gamma PPARγ and neuronal nitric oxide synthase nNOS. Results 24 h urine protein, serum urea nitrogen and creatinine of rats in model and telmisartan group were significantly higher than those in sham group （P 〈 0. 01 ） ; these indicators in telmisartan group was significantly lower than those in model group （P 〈 0.05）. The renal glomerular sclerosis and tubulointerstitial damage, glomerular sclerosis index and tubulointerstitial damage index of model group rats were significantly higher than those in sham-operated group （ P 〈 0. 01 ） ; these index in telmisartan group were significantly lower than those in model group （P 〈 0.05 ）. Compared with the shame group, the protein and mRNA expression of PPARγ and nNOS were significantly decreased in model group and telmisartan group（P 〈0. 05 ）, while the expression of PPARγ and nNOS in telmisartan group was significantly increased than that in model group （ P 〈 0.05 ）. Conclusions The 5/6 nephrectomy rats granted with telmisartan can significantly reduce glomerulosclerosis and the degree of renal interstitial fibrosis. The mechanism may be related to increased gene expression of PPAR＇y and nNOS.