Wang Yanxia, Wang Yan, Li Yong, Lu Linghong, Peng Yingxian, Zhang Shu, Xia Anzhou
Department of Pharmacology, Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China.
Department of Pharmacy, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China.
Exp Ther Med. 2020 Nov;20(5):17. doi: 10.3892/etm.2020.9144. Epub 2020 Aug 26.
Renal interstitial fibrosis (RIF) is a common pathological process that accompanies chronic kidney disease (CKD) and that progresses to end-stage renal failure (ESRD). Accumulating evidence has revealed that persistent mammalian target of rapamycin (mTOR) activation in kidneys is closely associated with the occurrence and progression of CKD. The DEP domain-containing mTOR interacting protein (Deptor) is an endogenous negative regulator of mTOR. Metformin can attenuate renal fibrosis in an animal model of diabetic nephropathy. Previous studies demonstrated that metformin can attenuate renal fibrosis in several models of CKD. However, the precise mechanisms of this effect are not well understood. The present study aimed to examine the mechanism of action of metformin on unilateral ureteral obstruction (UUO)-induced RIF in rats Sprague-Dawley rats were randomly divided into a sham-operated group, three UUO groups examined at different time points (3, 7 and 14 days after UUO surgery), and three metformin-treated groups, treated with three different concentrations of metformin. The metformin-treated groups were administered metformin orally every day for 14 consecutive days following surgery. The protein expression levels of Deptor, α-smooth muscle actin (α-SMA), phosphorylated (p-)mTOR, p-ribosomal protein S6 kinase (p-p70S6K) and CD68 were assessed. The present results suggested that, following UUO, there was a significant reduction of Deptor expression, and an increase in collagen deposition in the extracellular matrix over time, accompanied by an increased expression of several proteins including CD68, α-SMA, p-mTOR and p-p70S6K. Notably, metformin treatment reversed these effects. In conclusion, the present results suggested that metformin attenuated RIF of UUO rats, and the mechanism of action was found to be associated with the increase in Deptor expression and inhibition of the mTOR/p70S6K pathway in the kidneys of UUO rats.
肾间质纤维化（RIF）是一种常见的病理过程，伴随慢性肾脏病（CKD）发生，并进展至终末期肾衰竭（ESRD）。越来越多的证据表明，肾脏中持续的雷帕霉素靶蛋白（mTOR）激活与CKD的发生和进展密切相关。含DEP结构域的mTOR相互作用蛋白（Deptor）是mTOR的内源性负调节因子。二甲双胍可减轻糖尿病肾病动物模型中的肾纤维化。先前的研究表明，二甲双胍可减轻几种CKD模型中的肾纤维化。然而，这种作用的确切机制尚不完全清楚。本研究旨在探讨二甲双胍对单侧输尿管梗阻（UUO）诱导的大鼠肾间质纤维化的作用机制。将Sprague-Dawley大鼠随机分为假手术组、三个在不同时间点（UUO手术后3、7和14天）检查的UUO组，以及三个用三种不同浓度二甲双胍治疗的组。二甲双胍治疗组在手术后连续14天每天口服二甲双胍。评估Deptor、α-平滑肌肌动蛋白（α-SMA）、磷酸化（p-）mTOR、磷酸化核糖体蛋白S6激酶（p-p70S6K）和CD68的蛋白表达水平。目前的结果表明，UUO后，Deptor表达显著降低，细胞外基质中的胶原沉积随时间增加，同时包括CD68、α-SMA、p-mTOR和p-p70S6K在内的几种蛋白的表达增加。值得注意的是，二甲双胍治疗逆转了这些作用。总之，目前的结果表明，二甲双胍减轻了UUO大鼠的肾间质纤维化，其作用机制与Deptor表达增加以及抑制UUO大鼠肾脏中的mTOR/p70S6K途径有关。
