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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 To investigate the effects of candesartan, an angiotensin Ⅱ receptor antagonist, on renal oxidative stress in spontaneously type 2 diabetic KK / Ta mice and its possible mechanism. Methods KK / Ta mice were randomly divided into: untreated group; early treatment group: given candesartan (4 mg.kg-1d-1) orally from 6 weeks of age; advanced treatment group: Candesartan (4 mg.kg-1.d-1) was given at age. The normal control group used BALB / c mice. The 8-OHdG (8-OHdG), a marker of DNA oxidative damage in kidneys, was detected by immunohistochemistry. The mRNA and protein expression of p47phox subunit of NADPH oxidase were detected by immunohistochemistry and competitive RT-PCR. Simultaneous determination of urinary albumin excretion rate, blood pressure and glucose tolerance and other clinical indicators. Results Compared with BALB / c mice of the same age, urinary albumin excretion rate increased (P <0.01) and the expression of NADPH oxidase p47phox mRNA and protein increased in 28-week old KK / Ta mice (P <0.01) (P <0.01). Candesartan treatment reduced urinary albumin excretion (P <0.01), inhibited expression of NADPH oxidase p47phox mRNA and protein (P <0.01) and decreased formation of 8-OHdG (P <0.01) There was no significant difference between the two groups (P> 0.05). Conclusion Candesartan can delay the progression of diabetic nephropathy by down-regulating the expression of NADPH oxidase p47phox in diabetic rats.