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目的研究替米沙坦对糖尿病大鼠24 h尿蛋白、血肌酐、肌酐清除率(Ccr)和血清尿素氮(BUN)等相关代谢指标的影响,且应用基因芯片探讨替米沙坦改善肾功能的机制。方法 30只SD大鼠,其中随机选取10只为正常对照组(给予等体积生理盐水)。选用20只大鼠,采用STZ法制备糖尿病模型,而后将16只造模成功的糖尿病大鼠随机分为替米沙坦治疗组(给予10 mg/kg/d的替米沙坦,n=8)和糖尿病模型组(给予等体积生理盐水,n=8)。三组大鼠均连续灌胃12周。每4周测定大鼠空腹血糖(FBG)和体重。12周末测定大鼠24h尿蛋白、尿肌酐、血肌酐和BUN水平。12周末处死大鼠,取肾脏组织进行基因芯片实验,并运用real time PCR进行验证。结果糖尿病模型组24h尿蛋白(P<0.01)、血肌酐(P<0.05)和BUN(P<0.01)比对照组显著升高,Ccr较对照组显著降低(P<0.05)。替米沙坦能改善糖尿病大鼠24h尿蛋白、血肌酐、Ccr和BUN水平。基因芯片结果显示替米沙坦组较糖尿病模型组有1541个基因发生显著改变,其中554个上调,987个下调。基因富集分析显示这些差异表达基因集中在氧化磷酸化通路和PPAR通路。Real time PCR证实替米沙坦组较糖尿病模型组ATP合成酶β亚基(Atp5b)、细胞色素c氧化酶亚基VIc(Cox6c)和NADH脱氢酶(辅酶Q)铁硫蛋白3(Ndufs3)基因显著下调。结论替米沙坦能有效改善糖尿病大鼠肾脏功能。替米沙坦的肾脏改善作用可能是通过线粒体氧化磷酸化通路和PPAR-γ通路调节。
Objective To investigate the effects of telmisartan on 24 h urinary protein, serum creatinine, creatinine clearance (Ccr), serum urea nitrogen (BUN) and other related metabolic parameters in diabetic rats and to explore the effect of telmisartan on improving renal function Mechanisms. Methods Thirty SD rats were randomly divided into normal control group (given equal volume of normal saline). Twenty rats were selected and used to prepare diabetic model by STZ method. Sixteen diabetic rats were randomly divided into telmisartan treatment group (10 mg / kg / d telmisartan, n = 8 ) And diabetic model group (given equal volume of normal saline, n = 8). Three groups of rats were continuously gavage for 12 weeks. Fasting blood glucose (FBG) and body weight were measured every 4 weeks. Urine proteinuria, urinary creatinine, serum creatinine and BUN were measured at 12th week in rats. The rats were sacrificed on the 12th week, and the kidneys were taken for gene chip experiments and verified by real time PCR. Results The urinary protein (P <0.01), serum creatinine (P <0.05) and BUN (P <0.01) in diabetic model group were significantly higher than those in control group and Ccr was significantly lower than that in control group (P <0.05). Telmisartan can improve 24h urinary protein, serum creatinine, Ccr and BUN levels in diabetic rats. Gene chip results showed that telmisartan significantly changed 1541 genes in diabetic model group, of which 554 were up-regulated and 987 down-regulated. Gene enrichment analysis revealed that these differentially expressed genes were concentrated in the oxidative phosphorylation and PPAR pathways. Real time PCR confirmed that the telmisartan group had significantly higher ATP synthase β subunit (Atp5b), cytochrome c oxidase subunit VIc (Cox6c) and NADH dehydrogenase (Ndufs3) than the diabetic model group Genes were significantly down-regulated. Conclusion Telmisartan can effectively improve the renal function of diabetic rats. Telmisartan renal improvement may be mitochondrial oxidative phosphorylation and PPAR-γ pathway regulation.