Du Mengmeng, Wang Qingzhu, Li Wen, Ma Xiaojun, Wu Lina, Guo Feng, Zhao Shuiying, Huang Fengjuan, Wang Huanhuan, Qin Guijun
Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Biochem Biophys Res Commun. 2016 Mar 18;471(4):416-22. doi: 10.1016/j.bbrc.2016.02.066. Epub 2016 Feb 19.
Accumulating evidence has suggested that the epithelial-mesenchymal transition (EMT) is a pathway that potentially leads to podocyte depletion and proteinuria in diabetic nephropathy (DN). Therefore, this study was designed to investigate the protective effects of forkhead transcription factor O1 (FOXO1) on podocyte EMT, under high-glucose (HG) conditions in vitro and under diabetic conditions in vivo. The results showed that HG-induced podocyte EMT was associated with FOXO1 inactivation, which was accompanied by activation of the transforming growth factor (TGF)-β1/SMAD3/integrin-linked kinase (ILK) pathway. Accordingly, constitutive FOXO1 activation suppressed the TGF-β1/Smad3/ILK pathway and partially reversed EMT, similar to the effects observed after treatment with SIS3 or QLT0267, which are selective inhibitors of TGF-β1-dependent SMAD3 phosphorylation and ILK, respectively. In addition, lentiviral-mediated FOXO1 overexpression in the kidneys of diabetic mice considerably increased FOXO1 expression and activation, while decreasing proteinuria and renal pathological injury. These data suggested that forced FOXO1 activation inhibited HG-induced podocyte EMT and ameliorated proteinuria and renal injury in diabetic mice. Our findings further highlighted that FOXO1 played a protective role against diabetes in mice and may potentially be used as a novel therapeutic target for treating diabetic nephropathy.
越来越多的证据表明，上皮-间质转化（EMT）是一条可能导致糖尿病肾病（DN）中足细胞耗竭和蛋白尿的途径。因此，本研究旨在探讨叉头转录因子O1（FOXO1）在体外高糖（HG）条件下和体内糖尿病条件下对足细胞EMT的保护作用。结果表明，HG诱导的足细胞EMT与FOXO1失活有关，同时伴有转化生长因子（TGF）-β1/SMAD3/整合素连接激酶（ILK）途径的激活。相应地，组成性FOXO1激活抑制了TGF-β1/Smad3/ILK途径，并部分逆转了EMT，类似于分别用SIS3或QLT0267处理后观察到的效果，SIS3和QLT0267分别是TGF-β1依赖性SMAD3磷酸化和ILK的选择性抑制剂。此外，慢病毒介导的FOXO1在糖尿病小鼠肾脏中的过表达显著增加了FOXO1的表达和激活，同时降低了蛋白尿和肾脏病理损伤。这些数据表明，强制激活FOXO1可抑制HG诱导的足细胞EMT，并改善糖尿病小鼠的蛋白尿和肾损伤。我们的研究结果进一步强调，FOXO1在小鼠糖尿病中发挥保护作用，可能潜在地用作治疗糖尿病肾病的新治疗靶点。
