氯沙坦和辛伐他汀对糖尿病大鼠早期肾损伤的影响及其机制研究

Effects of losartan and simvastatin on early kidney injure of diabetic rats

目的探讨蛋白激酶C-β(PKC-β)和金属蛋白酶组织抑制物-1(TIMP-1)在糖尿病大鼠早期肾损伤中的作用以及氯沙坦和辛伐他汀肾脏保护作用的可能机制。方法将64只实验动物随机分为正常对照组、糖尿病组、氯沙坦治疗组、辛伐他汀治疗组及氯沙坦和辛伐他汀联合治疗组。链脲佐菌素(STZ)60 mg/kg制作糖尿病动物模型,8周后观察大鼠血糖、血脂、血肌酐1、2 h尿白蛋白排泄率(UAER)以及肾脏病理改变。并用免疫组织化学检测PKC-β、TIMP-1的表达。结果①两药均能减少UAER,改善肾脏肥大指数,联合治疗更为明显。②糖尿病对照组TIMP-1及PKC-β不同程度地表达于肾小球、肾小管及小管间质中,且较正常对照组的表达普遍增高(P<0.01)。两药均可显著抑制TIMP-1及PKC-β的表达(P<0.01),但均达不到正常对照水平,两药联合可使表达水平进一步下降和改善。结论氯沙坦和辛伐他汀对糖尿病早期肾损伤有一定的保护作用,其机制可能是通过下调PKC-β和TIMP-1,减少细胞外基质,减少尿蛋白实现的。

Objective To observe the mechanism of angiotensin Ⅱ receptor antagonist losartan and simvastatin in protecting the kidney of diabetic mrs. Methods Sixty-four experimental animals were randomly divided into 5 groups： normal control group; diabetic group （injected with streptozotocin in a dosage of 60 mg/kg）; diabetic rats treated with losartan; diabetic rats treated with simvastatin, and diabetic rats treated with losartan plus simvastatin. Plasma glucose, serum creatinine, urinary albumin, blood urea nitrogen （BUN） and profile of kidney hypertrophy were observed after an 8-week treatment, tissue inhibitor of metalloproteinase-l （TIMP-1） and protein kinase C-β（PKC-β） protein expression was measured by immunohistochemistry. Results Both losartan and simvastatin could reduce uninary albumin excretion rate （UAER） and kidney hypertrophy index. Combined treatment had better effect. The expression of TIMP-1, PKC-β in diabetic rats significantly increased than that in normal control group. Both losartan and simvastatin made the expression decreased, but not achieving the level of normal control. Combined treatment had better effect. Conclusion Losartan and simvastatin may have protective effect on kidney of diabetic rats,partly through down-regulating TIMP-1 and PKC-β expression, reducing extracellualar matrix and urine protein.