利拉鲁肽对糖尿病大鼠肾脏血管紧张素Ⅱ 1、2型受体表达的影响

Effects of liraglutide on expression of angiotension-Ⅱ type 1 and type 2 receptors in renal tissues of rats with diabetic nephropathy

目的:探讨利拉鲁肽对糖尿病大鼠肾脏血管紧张素Ⅱ1型受体(angiotensionⅡtype 1 receptor,AT-1R)、AT-2R表达的影响。方法:高脂高糖饲料喂养后小剂量链脲佐菌素(streptozocin,STZ)腹腔注射诱导建立2型糖尿病大鼠模型。雄性spraguedawley(SD)大鼠40只,随机分为3组:正常对照(normal control,NC)组10只、糖尿病(diabetic model,DM)组15只、利拉鲁肽(liraglutide,LR)组15只。DM组大鼠行生理盐水腹腔内注射,LR组及NC组予利拉鲁肽100μg/kg腹腔内注射干预2次/d。12周后采集各组大鼠血、尿标本测定大鼠尿蛋白排泄率(24 h urinary albumin excretion rate,UAER)、血尿素(blood urea nitrogen,BUN)、血肌酐(serum creatinine,Scr),采集肾组织标本行透射电镜观察并测定肾重/体重指数(kidney/body weight ratio,KW/BW)、平均肾小球体积(mean glomerular volume,MGV)、系膜面积比(fractional mesangial area,FMA);免疫组化法和逆转录聚合酶链反应法检测血管紧张素ⅡAT-1R、AT-2R在大鼠肾组织表达水平的改变。结果:利拉鲁肽可抑制糖尿病大鼠KW/BW、MGV、FMA、UAER、BUN与Scr的增加(P<0.05);可减轻足突融合、基底膜增厚、系膜增生等病理改变;可使大鼠肾脏组织AT-2R表达上调,而对AT-1R表达无明显影响(P<0.05)。结论:利拉鲁肽对糖尿病大鼠肾脏有保护作用,使肾脏组织内AT-1R/AT-2R的平衡倾向AT-2R可能是利拉鲁肽肾脏保护作用的机制之一。

Objective：To explore the effects of liraglutide on renal angiotension Ⅱ type 1 receptor（AT-1R） and angiotension II type 2receptor（AT-2R） of rats with type 2 diabetes. Methods：Forty adult male sprague-dawley rats were randomly separated into three groups：normal control group（NC）,diabetic model group（DM） and liraglutide group（LR）. The rats of DM and LR group received intraperitioneal injection of low dose of streptozotocin（STZ） after high fat and high glucose breeding to form an experimental model of type 2 diabetes. The rats of NC and LR group received liraglutide 100 ug/kg twice a day by hypodermic injection and the rats of DM group received injection of physiological saline. Twelve weeks after the build of type 2 diabetes model,the following indicators were assayed：（1）24 h urinary albumin excretion rate（UAER）,serum creatinine（Scr） and blood urea nitrogen（BUN）;（2）body weight（BW）,kidney weight（KW）,KW/BW,mean glomerular volume（MGV） and fractional mesangial area（FMA）;（3）the changes of pathologic feature of the kidney by periodic acid-silver methe-namine staining（PASM） and electron microscope;（4）the change of expression of AT-1R and AT-2R in kidney of rats by immunohistchemistry and RT-PCR. Results：（1）Liraglutide can markedly suppress the augmentation of KW/BW,MGV,FMA,Scr,BUN and UAER as well as attenuate the renal pathologic lesions such as podocyte foot process fuse and glomerular basement membrane（GBM） thickening.（2）Liraglutide can up-regulate the expression of AT-2R in the kidney of diabetic rats meanwhile has no evident effect on the expression of AT-1R. Conclusion：Mechanism of reno-protection of liraglutide may at least partly correlate with increased expression of AT-2R and change in balance of AT-1R/AT-2R of renal tissue.