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However, the molecular mechanisms whereby the loss\/loss-of-function of Polycystin 1 or 2 (PC1\/2) provokes fibrosis are largely unknown. The small GTPase RhoA has been recently implicated in cystogenesis, and we identified the RhoA\/cytoskeleton\/myocardin-related transcription factor (MRTF) pathway as an emerging mediator of epithelium-induced fibrogenesis. Therefore, we hypothesized that MRTF is activated by PC1\/2 loss and plays a critical role in the fibrogenic reprogramming of the epithelium. The loss of PC1 or PC2, induced by siRNA in vitro, activated RhoA and caused cytoskeletal remodeling and robust nuclear MRTF translocation and overexpression. These phenomena were also manifested in PKD1 (RC\/RC) and PKD2 (WS25\/\u2212) mice, with MRTF translocation and overexpression occurring predominantly in dilated tubules and the cyst-lining epithelium, respectively. In epithelial cells, a large cohort of PC1\/PC2 downregulation-induced genes was MRTF-dependent, including cytoskeletal, integrin-related, and matricellular\/fibrogenic proteins. Epithelial MRTF was necessary for the paracrine priming of the fibroblast\u2013myofibroblast transition. Thus, MRTF acts as a prime inducer of epithelial fibrogenesis in PKD. We propose that RhoA is a common upstream inducer of both histological hallmarks of PKD: cystogenesis and fibrosis.<\/jats:p>","DOI":"10.3390\/cells13110984","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T11:50:09Z","timestamp":1717588209000},"page":"984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Myocardin-Related Transcription Factor Mediates Epithelial Fibrogenesis in Polycystic Kidney Disease"],"prefix":"10.3390","volume":"13","author":[{"given":"Zsuzsanna","family":"Lichner","sequence":"first","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Ding","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarang","family":"Khare","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"},{"name":"Enrich Bioscience, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghong","family":"Dan","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0773-108X","authenticated-orcid":false,"given":"Raquel","family":"Benitez","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e9desz","family":"Praszner","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University Health Network, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1937-3101","authenticated-orcid":false,"given":"Rola","family":"Saleeb","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, Temerty School of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0526-393X","authenticated-orcid":false,"given":"Boris","family":"Hinz","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"},{"name":"Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"York","family":"Pei","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University Health Network, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2490-8422","authenticated-orcid":false,"given":"Katalin","family":"Sz\u00e1szi","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, Temerty School of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"},{"name":"Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s","family":"Kapus","sequence":"additional","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, ON M5B 1T8, Canada"},{"name":"Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada"},{"name":"Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41572-018-0047-y","article-title":"Polycystic kidney disease","volume":"4","author":"Bergmann","year":"2018","journal-title":"Nat. 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