Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, People's Republic of China.
Institute of Translational Medicine, China Medical University, Shenyang 110122, People's Republic of China.
Life Sci. 2019 Sep 1;232:116609. doi: 10.1016/j.lfs.2019.116609. Epub 2019 Jun 27.
Pioglitazone has been demonstrated to exert anti-fibrotic and renoprotective effects. But the detailed pharmacological mechanisms have not been clearly revealed. The present study aimed to investigate the possible mechanisms of pioglitazone in these two effects. TGF-β1-stimulated HK-2 cells and unilateral ureteral obstruction (UUO) mice were used as in vitro and in vivo models. The results showed that pioglitazone inhibited Smad-2/3 phosphorylation, upregulated Smad-7 expression and downregulated miR-21-5p expression in TGF-β1-exposed HK-2 cells. In addition, miR-21-5p inhibitors replicated the anti-fibrotic effects of pioglitazone, and miR-21-5p mimics inhibited these effects. In in vivo study, pioglitazone attenuated UUO-induced renal fibrosis and significantly decreased the expressions of pro-fibrotic proteins. Whereas, agomir of miR-21-5p inhibited the renoprotective function of pioglitazone in UUO mice. In conclusion, the present data suggest that modulation of miR-21-5p/Smad-7 signal may be involved in the anti-fibrotic effect of pioglitazone in the kidney of UUO mice.
吡格列酮已被证明具有抗纤维化和肾保护作用。但详细的药理机制尚未明确揭示。本研究旨在探讨吡格列酮在这两种作用中的可能机制。TGF-β1 刺激的 HK-2 细胞和单侧输尿管梗阻（UUO）小鼠被用作体外和体内模型。结果表明，吡格列酮抑制 TGF-β1 暴露的 HK-2 细胞中 Smad-2/3 的磷酸化，上调 Smad-7 的表达，下调 miR-21-5p 的表达。此外，miR-21-5p 抑制剂复制了吡格列酮的抗纤维化作用，而 miR-21-5p 模拟物抑制了这些作用。在体内研究中，吡格列酮减轻了 UUO 诱导的肾脏纤维化，并显著降低了促纤维化蛋白的表达。然而，miR-21-5p 的 agomir 抑制了吡格列酮在 UUO 小鼠中的肾保护作用。总之，本研究数据表明，miR-21-5p/Smad-7 信号的调节可能参与了吡格列酮在 UUO 小鼠肾脏中的抗纤维化作用。
