title: Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy.
abstract: Diabetic nephropathy (DN) is one of the most common complications associated with diabetes and characterized by renal microvascular injury along with accelerated synthesis of extracellular matrix proteins causing tubulointerstitial fibrosis. Production of type I collagen, the major component of extracellular matrix, is augmented during renal fibrosis after chronic exposure to hyperglycemia. However, the transcriptional modulator responsible for the epigenetic manipulation leading to induction of type I collagen genes is not clearly defined. We show here that tubulointerstitial fibrosis as a result of DN was diminished in myocardin-related transcription factor A (MRTF-A) -deficient mice. In cultured renal tubular epithelial cells and the kidneys of mice with DN, MRTF-A was induced by glucose and synergized with glucose to activate collagen transcription. Notably, MRTF-A silencing led to the disappearance of prominent histone modifications indicative of transcriptional activation, including acetylated histone H3K18/K27 and trimethylated histone H3K4. Detailed analysis revealed that MRTF-A recruited p300, a histone acetyltransferase, and WD repeat-containing protein 5 (WDR5), a key component of the histone H3K4 methyltransferase complex, to the collagen promoters and engaged these proteins in transcriptional activation. Estradiol suppressed collagen production by dampening the expression and binding activity of MRTF-A and interfering with the interaction between p300 and WDR5 in renal epithelial cells. Therefore, targeting the MRTF-A-associated epigenetic machinery might yield interventional strategies against DN-associated renal fibrosis.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology and.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, China;
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology and.
authors.forename: Hao
authors.initials: H
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology and.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Reproductive Medicine, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology and School of Basic Medical Sciences, Jiangnan University, Wuxi, China;
authors.forename: Junliang
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology and Department of Pathology and Pathophysiology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China; and.
authors.forename: Lina
authors.initials: L
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Reproductive Medicine, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology and Department of Medicine and Nursing, Jiangsu Jiankang Vocational University, Nanjing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology and yxu2005@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012313:RNA / Q000032:analysis; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D024042:Collagen Type I; C511173:Mrtfa protein, mouse; D015534:Trans-Activators; D012313:RNA
keywords: diabetic nephropathy; gene expression; regulation; renal fibrosis; transcription; transcription factors