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氯沙坦对糖尿病大鼠肾组织MMP-2、MMP-9、TIMP-1表达的影响
作者:史玉玲 程晓芸 吴国亭 张淑华 
单位:同济大学附属上海市第十人民医院,内分泌科,上海,200072
关键词:洛沙坦/药理学 糖尿病肾病 基质金属蛋白酶类 疾病模型 动物 大鼠 Sprague-Dawley 
分类号:R-332, R587.106, R977
出版年·卷·期(页码):2006·25·第一期(28-31)
摘要:

目的:研究血管紧张素Ⅱ受体拮抗剂氯沙坦对糖尿病大鼠肾组织中基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶-9(MMP-9)及金属蛋白酶组织抑制因子-1(TIMP-1)表达的影响.方法:将35只SPF级SD雄性成年大鼠随机分为正常对照组(C组,12只)、糖尿病组(DM组,11只)和糖尿病氯沙坦治疗组(DL组,12只).应用链脲佐菌素(STZ)诱导糖尿病模型后,对DL组应用氯沙坦灌胃治疗,其余2组灌等量蒸馏水.8周后,将35只大鼠一次性处死,取其肾脏,应用免疫组化法检测MMP-2、MMP-9及TIMP-1的表达情况.同时测定各组大鼠的血糖、糖化血红蛋白(HbA1c)、血肌酐、尿素氮、肌酐清除率及尿白蛋白排泄率.结果:DM组大鼠肾组织MMP-2、MMP-9的表达较C组明显下调(P<0.01),经氯沙坦治疗后的DL组表达明显上调(P<0.01),但仍低于C组(P<0.01);DM组大鼠肾组织TIMP-1的表达较C组明显上调(P<0.01),经氯沙坦治疗后的DL组表达明显下调(P<0.01),但仍高于C组(P<0.01).DM和DL两组间血糖、HbA1c无显著性差异(P>0.05),其余DL组指标值较DM组有所下降(P<0.05或P<0.01).结论:MMP-2、MMP-9、TIMP-1的表达变化与肾小球细胞外基质(ECM)降解减少相关,可能促进了糖尿病肾病的发生,氯沙坦可能通过干预这种表达变化减缓糖尿病肾病的发生和发展.

Objective To investigate the effect of losartan,a blocker of angiotensin Ⅱ type-1 receptor,on the expressions of matrix metalloproteinase-2(MMP2),matrix metalloproteinase-9(MMP9) and tissue inhibitor of metalloproteinase1((TIMP1)) in kidney tissues of rats with diabetes mellitus.Methods 35 SD male adult rats of SPF level 35 were divided into such 3 groups randomly as normal control group(C group,n=12),diabetes mellitus group(DM group,n=11) and losartan on diabetes mellitus rat group(DL group,n=12).After diabetes was induced by administrating streptozotocin(STZ),losartan was perfused into stomach of rats in DL group distilled water into stomach of other rats.After treatment of 8 weeks,35 rats were put to death once,their kidneys were removed for the study of the expressions of MMP2,MMP9,TIMP1 using StreptAvidin-Biotin Complex(SABC) immunohistochemistry method.The sections were scanned and analyzed by Motic Med 6.0 CMIAS medical colour picture analysis system.The blood glucose,glycosylated hemoglobin,serum creatinine,serum uria nitrogen,creatinine clearance rate and urinary albumin excretion rate were measured.Results Compared with C group,the expressions of MMP2 and MMP9 were decreased in DM group(P<0.01).The expressions of MMP2 and MMP9 in DL group werehigher than those in DM group(P<0.01),but they were still lower than those in C group((P<)0.01).Compared with C group,the expression of TIMP1 was increased in DM group(P<0.01).The expression of TIMP1 in DL group is lower than that in DM group(P<0.01),but it was still higher than that in C group((P<)0.01).Conclusion The changes of the expressions of MMP2,MMP9 and TIMP1 decrease the degradation extracellular matrix,which promote the occurrence and progress of diabetic nephropathy.Losartan may attenuate the occurrence and progress of diabetic nephropathy through intervening this change.

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