title: MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction.
abstract: Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemia-induced perturbation of renal tissue homeostasis. This study investigated whether regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 contributes to podocyte homeostasis and renal function in diabetic kidneys. Hyperglycemia accelerated podocyte injury and reduced nephrin, acetylated nephrin, and miR-29a levels in primary renal glomeruli from streptozotocin-induced diabetic mice. Diabetic miR-29a transgenic mice had better nephrin levels, podocyte viability, and renal function and less glomerular fibrosis and inflammation reaction compared with diabetic wild-type mice. Overexpression of miR-29a attenuated the promotion of HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion associated with diabetes and restored nephrin acetylation. Knockdown of miR-29a by antisense oligonucleotides promoted HDAC4 action, nephrin loss, podocyte apoptosis, and proteinuria in nondiabetic mice. In vitro, interruption of HDAC4 signaling alleviated the high glucose-induced apoptosis and inhibition of nephrin acetylation in podocyte cultures. Furthermore, HDAC4 interference increased the acetylation status of histone H3 at lysine 9 (H3K9Ac), the enrichment of H3K9Ac in miR-29a proximal promoter, and miR-29a transcription in high glucose-stressed podocytes. In conclusion, hyperglycemia impairs miR-29a signaling to intensify HDAC4 actions that contribute to podocyte protein deacetylation and degradation as well as renal dysfunction. HDAC4, via epigenetic H3K9 hypoacetylation, reduces miR-29a transcription. The renoprotective effects of miR-29a in diabetes-induced loss of podocyte integrity and renal homeostasis highlights the importance of post-translational acetylation reactions in podocyte microenvironments. Increasing miR-29a action may protect against diabetic podocytopathy.
authors.affiliation: Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan; Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan; School of Traditional Chinese Medicine and.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan;
authors.forename: Pei-Hsien
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan;
authors.forename: Yung-Chien
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan;
authors.forename: Chen-Chou
authors.initials: CC
authors.lastname: Lei
authors.affiliation: Departments of Orthopedic Surgery and Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan;
authors.forename: Jih-Yang
authors.initials: JY
authors.lastname: Ko
authors.affiliation: Departments of Orthopedic Surgery and.
authors.forename: Pei-Chin
authors.initials: PC
authors.lastname: Chuang
authors.affiliation: Department of Nephrology and.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Huang
authors.affiliation: Department of Nephrology and.
authors.forename: Shao-Yu
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Departments of Orthopedic Surgery and.
authors.forename: Shin-Long
authors.initials: SL
authors.lastname: Wu
authors.affiliation: Departments of Orthopedic Surgery and.
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
authors.forename: Wen-Chih
authors.initials: WC
authors.lastname: Chiang
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois; and.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Medical Research and Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, TaoYuan, Taiwan wangfs@ms33.hinet.net.
authors.forename: Feng-Sheng
authors.initials: FS
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006655:Histone Deacetylases / Q000502:physiology; D006657:Histones / Q000502:physiology; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D050199:Podocytes / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D006657:Histones; C547014:MIRN29 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C113267:nephrin; D006655:Histone Deacetylases