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目的探讨罗格列酮对肾间质纤维化的保护作用及其机制。方法以大鼠单侧输尿管梗阻(UUO)为模型,在不同的时间点(3d、7d、14d)观察梗阻侧肾间质基质含量;各组肾皮质间质巨噬细胞浸润情况;致纤维化的转化生长因子-β1(TGF-β1)的表达情况;肾皮质多种与肾脏纤维化相关的结缔组织生长因子(CTGF)、骨形态发生蛋白7(BMP7)、Smad6信号蛋白等的mRNA表达及BMP7、PAI1的蛋白表达。结果罗格列酮能改善UUO所致的肾间质纤维化程度(P<0.05);显著减少间质巨噬细胞浸润数量;下调肾脏组织TGF-β1的表达(P<0.05);减少TGF-β1下游致纤维化因子CTGF及PAI1的表达;同时上调TGF-β1信号传导中抑制性因子BMP7和Smad6的表达(P<0.05)。结论罗格列酮能保护UUO所致的肾间质炎症和纤维化损伤。其可能的作用机制包括抑制肾间质炎症细胞浸润;减少TGF-β1表达、阻止TGF-β信号传导、抑制TGF-β1下游效应因子CTGF和PAI1的表达,增加抗纤维化抗炎作用的BMP-7蛋白表达等,从而从多层面阻断TGF-β1的致纤维化作用。
Objective To investigate the protective effect of rosiglitazone on renal interstitial fibrosis and its mechanism. Methods Unilateral ureteral obstruction (UUO) was used as a model to observe the contents of interstitial matrix in obstructed side of renal interstitium at different time points (3d, 7d, 14d), the infiltration of interstitial macrophages in renal cortex, fibrosis (TGF-β1) in renal cortex and the expressions of connective tissue growth factor (CTGF), bone morphogenetic protein 7 (BMP7) and Smad6 signaling proteins in renal cortex BMP7, PAI1 protein expression. Results Rosiglitazone could improve the degree of renal interstitial fibrosis induced by UUO (P <0.05), significantly reduce the number of interstitial macrophages infiltration, and down-regulate the expression of TGF-β1 (P <0.05) β1 downstream fibroblasts CTGF and PAI1 expression; at the same time up-regulate TGF-β1 signaling inhibitory factor BMP7 and Smad6 expression (P <0.05). Conclusion Rosiglitazone can protect UUO-induced renal interstitial inflammation and fibrosis. Its possible mechanisms include inhibition of interstitial inflammatory cell infiltration; reduction of TGF-β1 expression, inhibition of TGF-β signaling, inhibition of TGF-β1 downstream effector factors CTGF and PAI1 expression, increased anti-fibrotic anti-inflammatory effects of BMP- 7 protein expression and so on, thus blocking TGF-β1 fibrosis from multiple levels.