title: Overexpression of FOXO1 ameliorates the podocyte epithelial-mesenchymal transition induced by high glucose in vitro and in vivo.
abstract: 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.
authors.affiliation: 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.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Du
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Fengjuan
authors.initials: F
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: hyqingj@zzu.edu.cn.
authors.forename: Guijun
authors.initials: G
authors.lastname: Qin
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000008:administration & dosage; D003893:Desmin / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D001391:Azo Compounds; D003893:Desmin; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005947:Glucose; D007546:Isoquinolines; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011725:Pyridines; D011758:Pyrroles; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D000099200:Scaffold Protein ILK; C508504:6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; C467200:Foxo1 protein, mouse; C552362:QLT 0267; C497791:Smad3 protein, mouse; C113267:nephrin
keywords: Diabetic nephropathy; Epithelial-mesenchymal transition; Forkhead transcription factor O1; Integrin-linked kinase; SMAD3; Transforming growth factor beta 1