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Abstract: FR-PO143

A Critical Role of Histone Methyltransferase EZH2 in Mediating Renal Epithelial-Mesenchymal Transition and Renal Fibrogenesis

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms


  • Zhou, Xiaoxu, Rhode Island Hospital, Brown University, Providence, Rhode Island, United States
  • Xiong, Chongxiang, Rhode Island Hospital, Brown University, Providence, Rhode Island, United States
  • Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States

EZH2 (Enhancer of Zeste Homolog 2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. Its role in renal epithelial-mesenchymal transition (EMT) remains unknown.


In this study, we examined the effect of EZH2 inhibition on EMT and renal fibrosis in the kidney following unilateral ureteral obstruction (UUO).


We found that EZH2 and H3K27me3 were highly expressed in the kidney of mice with and cultured mouse kidney proximal tubular cells (TKPT) undergoing EMT. Inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) attenuated renal fibrosis, which was associated with preserving E-cadherin expression and inhibiting vimentin upregulation in the obstructed kidney. Treatment with 3-DZNeP or transfection of EZH2 siRNA also inhibited TGF-β1-induced EMT of TKPT. Injury to the kidney or cultured TKPT resulted in upregulation of Snail1 and Twist, two transcription factors, and downregulation of PTEN, a protein tyrosine phosphatase associated with inhibition of PI3K-AKT signaling; EZH2 inhibition or silencing reversed all those responses. 3-DZNeP was also effective in suppressing epithelial arrest at G2/M phase and dephosphorylating AKT and β-catenin in in vivo and in vitro.


These data indicate that EZH2 activation contributes to renal EMT and fibrosis through activation of multiple signaling pathways and suggest that EZH2 would be a novel therapy for treatment of renal fibrosis.


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