1. Academic Validation
  2. Critical roles of SMYD2 lysine methyltransferase in mediating renal fibroblast activation and kidney fibrosis

Critical roles of SMYD2 lysine methyltransferase in mediating renal fibroblast activation and kidney fibrosis

  • FASEB J. 2021 Jul;35(7):e21715. doi: 10.1096/fj.202000554RRR.
Lirong Liu 1 2 3 Feng Liu 4 Yingjie Guan 1 Jianan Zou 1 Chunyun Zhang 1 Chongxiang Xiong 1 Ting C Zhao 5 George Bayliss 1 Xiaogang Li 6 Shougang Zhuang 1 4
Affiliations

Affiliations

  • 1 Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
  • 2 Center for Clinical Laboratories, the Affiliated Hospital of Guizhou Medical University, Guiyang, China.
  • 3 School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China.
  • 4 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 5 Department of Surgery, Rhode Island Hospital, Providence, RI, USA.
  • 6 Department of Medicine, Mayo Clinic, Rochester, MN, USA.
Abstract

SET and MYND domain protein 2 (SMYD2) is a lysine methyltransferase that mediates histone H3 lysine 36 trimethylation (H3K36me3) and acts as a regulator of tumorgenesis and cystic growth. 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- or TGF-β1-induced activation and proliferation of renal interstitial fibroblasts. Mechanistic studies showed that SMYD2 inhibition reduced phosphorylation of several profibrotic signaling molecules, including SMAD3, extracellular signal-regulated kinase 1/2, Akt, signal transducer and activator of transcription-3 and nuclear factor-κB 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-mesenchymal 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.

Keywords

SMYD2; Smad3; TGF-β1; proliferation; renal interstitial fibroblasts; unilateral ureteral obstruction.

Figures
Products