替米沙坦联合吡格列酮干预糖尿病肾病大鼠蛋白尿发生的机制

Mechanism of proteinuria prevention by combination of telmisartan and pioglitazone in diabetic nephropathy rats

目的观察替米沙坦联合吡格列酮对糖尿病肾病（DN）大鼠肾小球基底膜乙酰肝素酶（HPA）和足细胞podocin表达的影响，并探讨其可能机制。方法构建DN大鼠动物模型，将大鼠随机分为替米沙坦组（T组）、吡咯列酮组（B组）、替米沙坦＋吡格列酮联合组（L组）、DN组（D组）及健康对照组（N组）。12周后检测尿蛋白量（24h）及血生化指标，用RT—PCR和免疫组化检测HPA、podocinmRNA和蛋白的表达。结果灌胃12周后，L组尿蛋白量（24h）显著低于T组、B组，差异有统计学意义（P〈0．05）。与N组相比，T组、B组、L组、D组空腹血糖、相对肾质量、BUN、Scr均较高，差异有统计学意义（均P〈0．05）。L组的Scr显著低于T组、B组，差异具有统计学意义（均P〈0．05）。与N组相比，其余4组HPA蛋白表达较高，L组显著低于T组、B组；但其他4组podocin蛋白表达水平较低，L组显著高于T组、B组，差异均有统计学意义（均P〈0．05）。与N组相比，其他4组HPA和podocinmRNA表达量较高，L组HPAmRNA表达显著低于T组、B组，podocinmRNA表达显著高于T组、B组，差异均有统计学意义（均P〈0．05）。结论替米沙坦联合吡格列酮较单用药显著减轻DN大鼠早期蛋白尿，此作用可能通过下调DN肾小球基底膜HPA，上调足细胞podocin蛋白的表达实现。

Objective To study the combination effects of telmisartan and pioglitazone on the expression of heparanases （HPA） and podocin in the kidney of diabetic nephropathy （DN） rats and its possible mechanism. Methods DN model rats were established by intraperitoneal injection with STZ for 12 weeks. All the DN rats were randomly divided into telmisartan group （T group）, pioglitazone group （P group）, combination of telmisartan and pioglitazone group （L group）, and DN group （D group）. Healthy rats were chosen as healthy control group（N group）. After garage with drugs for 12 weeks, 24-h urinary protein and serum biochemical indicators were examined. RT-PCR and immunohistochemistry methods were applied to detect the mRNA and protein expression of HPA and podocin. Results Compared with T group and P group, 24-b urinary protein of L group was markedly decreased（P〈0.05）. Compared with the N group, the level of fasting blood glucose, relative renal weight, BUN and Scr in other 4 groups were markedly increased （P〈0.05）. Compared with T group and P group, the Scr level and the expression of HPA mRNA and protein in L group was markedly decreased （P〈0.05）, and the protein and mRNA expression of podocin in L group was markedly increased （P〈0.05）. Conclusion Combination of telmisartan and pioglitazone can down-regulate the mRNA and protein expression of HPA of glomerular basement membrane and up-regulate the protein expression of podocin of podocyte in DN rats, which may ameliorate the proteinuria.