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However, its role in renal fibrosis remains unknown. In this study, we found that SMYD2 was highly expressed in the murine kidney of renal fibrosis induced by unilateral ureteral obstruction, and primarily located in interstitial fibroblasts and renal tubular epithelial cells. Pharmacological inhibition of SMYD2 with AZ505, a highly selective inhibitor of SMYD2, protected against renal fibrosis and inhibited activation\/proliferation of renal interstitial fibroblasts and conversion of epithelial cells to a profibrotic phenotype in this model. In cultured renal interstitial fibroblasts, treatment with AZ505 or silencing of SMYD2 by specific siRNA also inhibited serum\u2010 or TGF\u2010\u03b21\u2010induced activation and proliferation of renal interstitial fibroblasts. Mechanistic studies showed that SMYD2 inhibition reduced phosphorylation of several profibrotic signaling molecules, including Smad3, extracellular signal\u2010regulated kinase 1\/2, AKT, signal transducer and activator of transcription\u20103 and nuclear factor\u2010\u03baB in both injured kidney and cultured renal fibroblasts. AZ505 was also effective in suppressing renal expression of Snail and Twist, two transcriptional factors that mediate renal partial epithelial\u2010mesenchymal transition and fibrosis. Conversely, AZ505 treatment prevented downregulation of Smad7, a renoprotective factor in vivo and in vitro. These results indicate that SMYD2 plays a critical role in mediating conversion of epithelial cells to a profibrotic phenotype, renal fibroblast activation and renal fibrogenesis, and suggest that SMYD2 may be a potential target for the treatment of chronic fibrosis in kidney disease.<\/jats:p>","DOI":"10.1096\/fj.202000554rrr","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T08:45:07Z","timestamp":1624005907000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Critical roles of SMYD2 lysine methyltransferase in mediating renal fibroblast activation and kidney fibrosis"],"prefix":"10.1096","volume":"35","author":[{"given":"Lirong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Medicine Rhode Island Hospital and Alpert Medical School Brown University Providence RI USA"},{"name":"Center for Clinical Laboratories the Affiliated Hospital of Guizhou Medical 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