title: Activation of FoxO1/ PGC-1α prevents mitochondrial dysfunction and ameliorates mesangial cell injury in diabetic rats.
abstract: The generation of hyperglycemia-induced mitochondrial reactive oxygen species (ROS) is a key event in diabetic nephropathy development. The forkhead-box class O1 (FoxO1) and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) proteins are implicated in oxidative stress. We investigated the in vivo association of FoxO1 and PGC-1α in renal cortices from streptozotocin-induced diabetic rats and in rat kidney mesangial cells (MCs) treated with high glucose, in vitro. High-glucose induced FoxO1 inhibition was associated with decreased PGC-1α expression in MCs. These changes were accompanied by mitochondrial dysfunction and increased ROS generation. However, constitutive FoxO1 activation increased PGC-1α expression and partially reversed these changes, which were significantly decreased by the treatment of PGC-1α-small interfering RNA. We identified PGC-1α as a direct FoxO1 transcriptional target by chromatin immunoprecipitation. In addition, lentiviral-mediated FoxO1 overexpression in diabetic-rat kidneys significantly increased PGC-1α, NRF-1, and Mfn2 expression, and decreased malondialdehyde production and proteinuria. These data suggest that FoxO1/PGC-1α activation protected rats against high-glucose-induced MC injury by attenuating mitochondrial dysfunction and cellular ROS production.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, 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: Lina
authors.initials: L
authors.lastname: Wu
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, 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: Yingni
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, 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: Hongfei
authors.initials: H
authors.lastname: Ji
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ma
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, 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; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000071161:Forkhead Box Protein O1
chemical_list: D051858:Forkhead Transcription Factors; D020558:GTP Phosphohydrolases; D005947:Glucose; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C501429:Ppargc1a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C489710:Mfn2 protein, rat
keywords: Diabetic nephropathy; Forkhead box class O1; Oxidative stress; Peroxisome proliferator-activated receptor γ co-activator 1α