坎地沙坦抑制2型糖尿病KK/Ta小鼠肾脏氧化应激反应  

Candesartan Inhibits Oxidative Stress in Type 2 Diabetic KK/Ta Mouse Kidneys

作　　者：范秋灵[1] 李卅立[1] 蒲实[1] 董雪竹[1] 张玉侠[1] 冯江敏[1] 马健飞[1] 姜奕[1] 王力宁[1] 

机构地区：[1]中国医科大学附属第一医院肾内科,沈阳110001

出　　处：《中国医科大学学报》2012年第5期391-395,共5页Journal of China Medical University

基　　金：国家自然科学基金资助项目(30700369);教育部留学回国人员科研启动基金资助项目(教外司留[2006]331号);辽宁省教育厅高校科研计划(L2010658);沈阳市科技计划项目(F11-264-1-38)

摘　　要：目的探讨血管紧张素Ⅱ受体拮抗剂坎地沙坦治疗对自发性2型糖尿病KK/Ta小鼠肾脏氧化应激的影响及其作用机制。方法糖尿病KK/Ta小鼠随机分为:非治疗组;早期治疗组:自6周龄起经口给予坎地沙坦(4 mg.kg-.1d-1);晚期治疗组:自12周龄起给予坎地沙坦(4 mg.kg-1.d-1)。正常对照组采用BALB/c小鼠。应用免疫组化染色检测肾脏中DNA氧化损伤的标志物8-羟基脱氧鸟苷(8-OHdG),免疫组化和竞争性RT-PCR检测NADPH氧化酶p47phox亚基mRNA和蛋白的表达。同时测定尿白蛋白排泄率、血压和糖耐量等临床指标。结果与同龄BALB/c小鼠比较,28周龄KK/Ta小鼠尿白蛋白排泄率增加(P<0.01),肾脏NADPH氧化酶p47phox的mRNA和蛋白表达上调(P<0.01),8-OHdG的形成增加(P<0.01)。坎地沙坦治疗减少尿白蛋白排泄率(P<0.01),抑制肾脏NADPH氧化酶p47phox mRNA和蛋白的表达(P<0.01),减少8-OHdG的形成(P<0.01),早期治疗组和晚期治疗组的作用无统计学差异(P>0.05)。结论坎地沙坦治疗通过下调糖尿病状态下肾脏NADPH氧化酶p47phox的表达,抑制氧化应激反应,延缓糖尿病肾病的进展。Objective Oxidative stress induced by angiotensin II plays a crucial role in the pathogenesis of diabetic nephropathy.The effects of candesartan,an angiotensin II type 1 receptor blocker（ARB）,were investigated on oxidative stress in type 2 diabetic KK/Ta mouse kidneys.Methods KK/Ta mice divided into three groups were treated with candesartan（4 mg·kg-1·d-1） or vehicle from 6 or 12 to 28 weeks of age.Control BALB/c mice were followed concurrently.Body weight,blood pressure,blood glucose,urinary microalbumin,urinary creatinine and serum creatinine were measured every four weeks.At 28 weeks,renal expressions of the p47phox component of NADPH oxidase and 8-OHdG and nitrotyrosine were evaluated by immunohistochemistry and/or by competitive RT-PCR.Results Body weight,blood glucose,hypertension,and urinary microalbumin/creatinine ratio of KK/Ta mice at 28 weeks of age were significantly higher than those of BALB/c mice（P 〈0.01）.Protein and mRNA expressions of p47phox were up-regulated in KK/Ta kidneys（P 〈 0.01） with increased immunostaining intensities of 8-OHdG（P 〈 0.01）.Treatment with candesartan down-regulated the protein and mRNA expressions of p47phox（P 〈 0.001） and decreased the formation of 8-OhdG（P 〈 0.01）,albuminuria（P 〈 0.01） and mean blood pressure of KK/Ta mice at 28 weeks of age（P 〈 0.05）.There was no significant difference between the two treatment groups（from 6 or 12 weeks,P 〉 0.05）.Conclusion The results suggest that candesartan,an ARB,reduces oxidative stress and subsequent albuminuria by down-regulating NADPH oxidase p47phox in type 2 diabetic KK/Ta mouse kidneys.

关 键 词：糖尿病肾病 坎地沙坦 KK/Ta小鼠 氧化应激 NADPH氧化酶p47phox 

分 类 号：R587.2[医药卫生—内分泌]