PMID- 30121256 OWN - NLM STAT- MEDLINE DCOM- 20190812 LR - 20211204 IS - 1525-2191 (Electronic) IS - 0002-9440 (Linking) VI - 188 IP - 10 DP - 2018 Oct TI - DNA Methylation Reduces the Yes-Associated Protein 1/WW Domain Containing Transcription Regulator 1 Pathway and Prevents Pathologic Remodeling during Bladder Obstruction by Limiting Expression of BDNF. PG - 2177-2194 LID - S0002-9440(17)31038-6 [pii] LID - 10.1016/j.ajpath.2018.06.024 [doi] AB - Chronic bladder obstruction and bladder smooth muscle cell (SMC) stretch provide fibrotic and mechanical environments that can lead to epigenetic change. Therefore, we examined the role of DNA methylation in bladder pathology and transcriptional control. Sprague-Dawley female rats underwent partial bladder obstruction by ligation of a silk suture around the proximal urethra next to a 0.9-mm steel rod. Sham operation comprised passing the suture around the urethra. After 2 weeks, rats were randomized to normal saline or DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (DAC) at 1 mg/kg, three times/week intraperitoneally. After 6 weeks, bladders were weighed and divided for histology and RNA analysis by high-throughput real-time quantitative PCR arrays. DAC treatment during obstruction in vivo profoundly augmented brain-derived neurotrophic factor (BDNF) expression compared with the obstruction with vehicle group, which was statistically correlated with pathophysiologic parameters. BDNF, cysteine rich angiogenic inducer 61 (CYR61), and connective tissue growth factor (CTGF) expression clustered tightly together using Pearson's correlation analysis. Their promoters were associated with the TEA domain family member 1 (TEAD1) and Yes-associated protein 1/WW domain containing transcription regulator 1 pathways. Interestingly, DAC treatment increased BDNF expression in bladder SMCs (P < 0.0002). Stretch-induced BDNF was inhibited by the YAP/WWTR1 inhibitor verteporfin. Verteporfin improved the SMC phenotype (proliferative markers and SMC marker expression), in part by reducing BDNF. Expression of BDNF is limited by DNA methylation and associated with pathophysiologic changes during partial bladder outlet obstruction and SMC phenotypic change in vitro. CI - Copyright (c) 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Sidler, Martin AU - Sidler M AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Urology Division, Department of Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Aitken, Karen J AU - Aitken KJ AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Urology Division, Department of Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Jiang, Jia-Xin AU - Jiang JX AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Physiology, Faculty of Arts and Sciences, University of Toronto, Toronto, Ontario, Canada. FAU - Sotiropoulos, Chris AU - Sotiropoulos C AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Physiology, Faculty of Arts and Sciences, University of Toronto, Toronto, Ontario, Canada. FAU - Aggarwal, Prateek AU - Aggarwal P AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Human Biology Program, University of Toronto, Toronto, Ontario, Canada. FAU - Anees, Arsalan AU - Anees A AD - Department of Physiology, Faculty of Arts and Sciences, University of Toronto, Toronto, Ontario, Canada. FAU - Chong, Cynthia AU - Chong C AD - Human Biology Program, University of Toronto, Toronto, Ontario, Canada. FAU - Siebenaller, Aliza AU - Siebenaller A AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Thanabalasingam, Thenuka AU - Thanabalasingam T AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Human Biology Program, University of Toronto, Toronto, Ontario, Canada. FAU - White, J Maxwell AU - White JM AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; School of Business, Queen's University, Kingston, Ontario, Canada. FAU - Choufani, Sanaa AU - Choufani S AD - Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Weksberg, Rosanna AU - Weksberg R AD - Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. FAU - Sangiorgi, Bruno AU - Sangiorgi B AD - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada. FAU - Wrana, Jeff AU - Wrana J AD - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada. FAU - Delgado-Olguin, Paul AU - Delgado-Olguin P AD - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; Translational Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Heart and Stroke/Richard Leward Centre of Excellence in Cardiovascular Research, Toronto, Ontario, Canada. FAU - Bagli, Darius J AU - Bagli DJ AD - Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Urology Division, Department of Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, Faculty of Arts and Sciences, University of Toronto, Toronto, Ontario, Canada. Electronic address: darius.bagli@sickkids.ca. LA - eng GR - CIHR/Canadian Institutes of Health Research/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180817 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Bdnf protein, rat) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (CCN1 protein, rat) RN - 0 (CCN2 protein, rat) RN - 0 (Cysteine-Rich Protein 61) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Transcriptional Coactivator with PDZ-Binding Motif Proteins) RN - 0 (WWTR1 protein, rat) RN - 0X9PA28K43 (Verteporfin) RN - 139568-91-5 (Connective Tissue Growth Factor) RN - EC 2.7.10.2 (Proto-Oncogene Proteins c-yes) RN - EC 2.7.10.2 (Yes1 protein, rat) MH - Animals MH - Brain-Derived Neurotrophic Factor/*antagonists & inhibitors MH - Cells, Cultured MH - Connective Tissue Growth Factor/metabolism MH - Cysteine-Rich Protein 61/metabolism MH - DNA Methylation/*physiology MH - Female MH - Intracellular Signaling Peptides and Proteins/*metabolism MH - Myocytes, Smooth Muscle/physiology MH - Proto-Oncogene Proteins c-yes/*metabolism MH - Rats, Sprague-Dawley MH - Stress, Mechanical MH - Transcriptional Coactivator with PDZ-Binding Motif Proteins MH - Urinary Bladder Neck Obstruction/*physiopathology MH - Verteporfin/pharmacology MH - WW Domains/physiology EDAT- 2018/08/20 06:00 MHDA- 2019/08/14 06:00 CRDT- 2018/08/20 06:00 PHST- 2017/10/31 00:00 [received] PHST- 2018/05/25 00:00 [revised] PHST- 2018/06/26 00:00 [accepted] PHST- 2018/08/20 06:00 [pubmed] PHST- 2019/08/14 06:00 [medline] PHST- 2018/08/20 06:00 [entrez] AID - S0002-9440(17)31038-6 [pii] AID - 10.1016/j.ajpath.2018.06.024 [doi] PST - ppublish SO - Am J Pathol. 2018 Oct;188(10):2177-2194. doi: 10.1016/j.ajpath.2018.06.024. Epub 2018 Aug 17.