Valsartan对糖尿病肾病肾保护作用的实验研究

Study on Renoprotective Effects of Valsartan in Experimental Diabetic Rats

目的 :探讨血管紧张素Ⅱ受体拮抗剂 (AT1RA)Valsartan对糖尿病大鼠肾脏基质金属蛋白酶 - 2 (MMP- 2 )及其抑制物 (TIMP - 2 )表达的影响。方法 :大鼠随机分为正常对照组 (A组 )、糖尿病组 (B组 )及治疗组 (C组 ) ,大鼠腹腔单剂量注射链脲佐菌素 (streptozotocin ,STZ) 6 5mg/kg建立糖尿病动物模型。治疗组给予Valsartan(缬沙坦 ) 10mg·kg-1·d-1灌胃。第 3周、第 6周各组分别宰杀 6只 ,检测肌酐清除率、尿白蛋白排泄率及肾重 /体重 ,免疫组织化学染色检测肾小球MMP - 2、TIMP - 2、纤维连接蛋白和Ⅳ型胶原表达。结果 :治疗组肌酐清除率 (P <0 .0 5 )、尿白蛋白排泄率 (P <0 .0 5 ,P <0 .0 1)及肾重 /体重 (P <0 .0 5 )均低于糖尿病组。免疫组织化学染色可见糖尿病大鼠肾小球TIMP - 2、纤维连接蛋白和Ⅳ型胶原表达明显增加 (P <0 .0 5 ,P <0 .0 1)。在治疗组 ,上述明显增加的表达均受到明显抑制 (P <0 .0 5 )。MMP - 2在糖尿病大鼠肾小球的表达明显被抑制 (P <0 .0 1) ,治疗组其表达明显增加 (P <0 .0 5 )。结论 :Valsartan通过上调糖尿病大鼠肾小球MMP - 2表达、下调TIMP - 2表达 ,对糖尿病大鼠肾脏病变有部分保护作用。

Objective:To investigate the renoprotective effects of angiotensin Ⅱ type 1 receptor antagonist valsartan in STZ-induced diabetic rats.Methods:The following groups of rats were studied:normal control rats,STZ-induced diabetic rats and diabetic rats treated with valsartan(10 mg·kg -1 ·d -1 ).Urinary albumin excretion rate,creatinine clearance rate as well as profile of kidney hypertrophy were observed after 3,6 weeks of treatment,while MMP-2,TIMP-2,FN and collagen Ⅳ protein expressions were measured by immunohistological staining.In addition,renal tissues were studied by light microscopy .Results:Kidney /body weight ratio( P <0.05, P <0.01),creatinine clearance rate( P <0.05),and urinary albumin excretion rate( P <0.05, P <0.01)in diabetic rats treated with valsartan were significantly lower than those in untreated diabetic rats after 3,6 weeks. Compared to non-diabetic rats,the protein expressions of TIMP-2( P <0.01),FN( P < 0.05 , P <0.01),and collagen Ⅳ( P <0.05, P <0.01) siguificautly increased in glomeruli,while MMP-2( P <0.01) protein was siguificautly reduced in untreated-diabetic rats after 3,6 weeks. The abnormal levels of these proteins were partly reversed In diabetic rats treated by valsartan ( P <0.05).Accordingly, renal histopathological changes and functional lesions observed in diabetic rats were drawatically suppressed by valsartan freatmeat.Conclusion:Valsartan has some renoprotective effects in experimental diabetic rats,partly through up-regulation MMP-2 and down-regulation TIMP-2 activity in glomeruli.