title: Protective effects of miR-29a on diabetic glomerular dysfunction by modulation of DKK1/Wnt/β-catenin signaling.
abstract: Dysregulation of specific microRNAs or Wnt/β-catenin signaling pathway is critically implicated in the pathogenesis of various renal diseases. However, the relationship between microRNAs and Wnt/β-catenin signaling in diabetes-induced glomerular sclerosis remains unknown. Here, we found that decreased miR-29a expression and attenuated Wnt/β-catenin signaling were concomitantly detected in glomeruli of streptozotocin-induced diabetic mice. Gain of miR-29a function in diabetic mice substantially increased the expression of β-catenin and blocked the expressions of profibrotic gene markers, including DKK1 (a Wnt antagonist), TGF-β1 and fibronectin, in glomerular mesangium. Moreover, in the normal mice treated with miR-29a inhibitor, renal fibrosis was induced with an attenuated Wnt/β-catenin signaling activity. Consistently, the constructed miR-29a transgenic mice that supported sustained Wnt/β-catenin signaling had the ability to block the expressions of profibrotic genes after induction of diabetes. We also demonstrated that miR-29a acts as a positive regulator of Wnt/β-catenin signaling in cultured mesangial cells and functions to protect cell apoptosis and fibrosis. Importantly, we showed that activation of Wnt/β-catenin signaling in cultured mesangial cells by transfecting the β-catenin (Δ45) mutant or by a GSK-3β inhibitor reversely upregulated miR29a. Our findings suggest that the reciprocal relationship between miR-29a and DKK1/Wnt/β-catenin signaling may play an important part in protecting renal fibrogenesis.
authors.affiliation: Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan.|Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yung-Chien
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Colleage of Medicine, Chang Gung University, Taiwan.|Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan.|Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Pey-Jium
authors.initials: PJ
authors.lastname: Chang
authors.affiliation: Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ho
authors.affiliation: Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Huang
authors.affiliation: Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan.|Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Ya-Hsueh
authors.initials: YH
authors.lastname: Shih
authors.affiliation: Center for Shockwave Medicine and Tissue Engineering, Department of Medical Research, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Ching-Jen
authors.initials: CJ
authors.lastname: Wang
authors.affiliation: Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan.|Colleage of Medicine, Chang Gung University, Taiwan.|Center for Shockwave Medicine and Tissue Engineering, Department of Medical Research, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D050527:Mesangial Cells / Q000473:pathology; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D051176:beta Catenin