不同剂量氯沙坦对防治肾间质纤维化效果的影响

The effects of different doses of losartan in the experiment renal interstitial fibrosis

目的:观察血管紧张素Ⅱ受体拮抗剂(ARBs)氯沙坦对大鼠单侧输尿管梗阻(UUO)模型肾间质纤维化的影响,探讨超大剂量能否优于常规剂量起到更多的肾脏保护作用。方法:建立大鼠UUO模型,术后3d分为常规剂量治疗组、超大剂量治疗组、UUO组和假手术组。药物干预组分别每天给予氯沙坦50mg/kg、氯沙坦500mg/kg灌胃,假手术组及UUO组每天给予同体积生理盐水灌胃。观察模型第7、14和21天鼠尾袖带血压(TCP)、24h尿蛋白、肾小管损害程度、肾间质纤维化程度、肾间质巨噬细胞数和转化生长因子-β1(TGF-"1)mRNA的表达。结果:随着梗阻时间延长,UUO组TCP逐渐增高、24h尿蛋白、肾间质纤维化程度、肾小管损害程度及肾间质巨噬细胞浸润显著增加,TGF-β1mRNA含量明显增加,与其余各组相比差异有显著性(P<0.05)。同时,超大剂量氯沙坦相对于常规剂量,能更有效地控制血压、减少蛋白尿、减轻肾小管损害和肾间质纤维化、减少肾间质单核巨噬细胞浸润,显著抑制TGF-β1mRNA表达。结论:超大剂量氯沙坦在UUO大鼠模型中较常规剂量起到了更多的肾脏保护作用。

Objective To investigate the effects of angiotensin receptor blockade （ARB）, losartan on tubulointerstitial fibrosis of rat unilateral ureteral obstruction （UUO） model, and to study whether the use of an extremely high dose would exert a superior renoprotective effect than conventional doses. Methods Rats were randomly assigned to conventional dose and extremely high dose of losartan treatment group 3 days after UUO, sham-operated group and operation group. Two treatment groups were administered orally a daily dose of losartan 50 mg/kg or 500 mg/kg by gastric garage. Sham-operated group and operation group received the same volume physiological saline. Daily urinary albumin excretion （UalbV）, tail-cuff pressure （TCP）, the percentage of renal tubular lesions, fractional interstitial area （%INT）, macrophage infiltration and the expression of transforming growth factor（TGF）-β1 mRNA were assessed at day 7,14 and 21. Results The rate of TCP and UalbV, the percentage of tubular lesions and interstitial fibrosis, the number of interstitial macrophages and the expression of TGF-β1 mRNA were significantly increased after renal obstruction in comparison with other groups（P 〈 0.05）. Furthermore,in comparison with conventional dose, the extremely high dose treatment significantly reduced TCP and UalbV, attenuated interstitial fibrosis and tubular lesions, suppressed macrophages infiltration and the expression of TGF-β1 mRNA. Conclusion The extremely high dose of ARB, losartan affords superior renoprotection compared to treatment with conventional doses in UUO model.