Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts.
Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts.
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DOI：
10.3390/ijms17020146
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发表时间：
2016-01-22
影响因子：
5.6
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Shen Y;Miao N;Xu J;Gan X;Xu D;Zhou L;Xue H;Zhang W;Lu L
肾脏纤维化是慢性肾脏疾病(CKD)的最终共同途径，临床上尚无有效的药物来控制其进展。二甲双胍最初是作为一种抗糖尿病药物开发的，最近因其在治疗其他疾病方面的潜力而受到关注。在本研究中，我们在体内单侧输尿管梗阻(UUO)小鼠模型和血管紧张素II(Ang II)处理的肾成纤维细胞NRK-49F细胞中观察了其对肾脏纤维化的影响。我们的研究结果表明，UUO诱导了肾脏纤维化，并与ERK信号通路的激活、纤维连接蛋白、I型胶原和转化生长因子-β(TGFR-β)的表达上调有关。二甲双胍可抑制ERK信号通路的激活，减少梗阻肾脏细胞外基质(ECM)蛋白的产生和胶原沉积。在培养的肾成纤维细胞中，Ang II以时间依赖的方式增加纤维连接蛋白和I型胶原的表达，并激活ERK信号和转化生长因子-β。二甲双胍可阻断血管紧张素Ⅱ诱导的ERK信号的激活和细胞外基质的过度产生。我们的结果表明，二甲双胍可能通过抑制ERK信号通路来预防肾纤维化，并可能成为治疗肾纤维化的一种新策略。
Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) in vivo and in angiotensin II (Ang II)–treated renal fibroblast NRK-49F cells in vitro. Our data showed that UUO induced renal fibrosis and combined with the activation of ERK signaling, the upregulation of fibronectin, collagen I, and transforming growth factor-β (TGF-β). The administration of metformin inhibited the activation of ERK signaling and attenuated the production of extracellular matrix (ECM) proteins and collagen deposition in the obstructed kidneys. In cultured renal fibroblasts, Ang II increased the expression of fibronectin and collagen I and also activated ERK signaling and TGF-β in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II–induced ERK signaling activation and ECM overproduction. Our results show that metformin prevents renal fibrosis, possibly through the inhibition of ERK signaling, and may be a novel strategy for the treatment of renal fibrosis.