Overexpression of FOXO1 ameliorates the podocyte epithelial–mesenchymal transition induced by high glucose in vitro and in vivo

• DOI: 10.1016/j.bbrc.2016.02.066
• Publication Date: 2016-02-20T14:18:10Z
• Authors: Mengmeng Du; Qingzhu Wang; Wen Li; Xiaojun Ma; Lina Wu; Feng Guo; Shuiying Zhao; Fengjuan Huang; Huanhuan Wang; Guijun Qin
• Keywords: Male; 0303 health sciences; Epithelial-Mesenchymal Transition; Forkhead Box Protein O1; Podocytes; Pyridines; Membrane Proteins; Forkhead Transcription Factors; Protein Serine-Threonine Kinases; Isoquinolines; Desmin; Diabetes Mellitus, Experimental; 3. Good health; Mice; 03 medical and health sciences; Glucose; Gene Expression Regulation; Animals; Pyrazoles; Diabetic Nephropathies; Pyrroles; Smad3 Protein; Azo Compounds

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.