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Abstract: FR-PO1053

Deletion of EZH2 from Renal Tubular Cells and Stroma-Derived Interstitial Cells Protects Mice from Kidney Fibrosis by Inhibition of Notch Signaling and Preservation of Klotho and BMP7 Expression

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Yu, Chao, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, Shanghai, China
  • Zhuang, Shougang, Brown University Warren Alpert Medical School, Providence, Rhode Island, United States

Although histone methyltransferase enhancer of zeste homolog 2 (EZH2) was denovo expressed in multiple cell types in the injured kidney, the contribution of EZH2 in specific cell type to renal fibrosis and the underlying mechanism remains poorly defined.


Mice with deletion of EZH2 from renal interstitial fibroblasts or renal tubular cells were generated and subjected to unilateral ureteral obstruction (UUO) to investigate renal fibrotic changes and signaling mechanisms and in comparison with the effect of EZH2 inhibitors. Chromatin immunoprecipitation was performed to analyze the association of EZH2 and H3K37 with Notch1 and Notch 3 as well as klotho and BMP7 promoters, respectively.


Compared with wild type, mice with conditional deletion of EZH2 in renal interstitial cells or in renal tubular cells developed less renal fibrosis following UUO injury. Tubule-specific deletion of EZH2 was associated reduced expression of vimentin and Snail and preserved expression of E-cadherin. Genetic depletion of EZH2 in either cell type or pharmacological inhibition of EZH2 reduced injury –induced expression of Notch1 and Notch3, active form of Notch1 and their signaling components Jagged-1, Hes1 and Hes2. In wild-type mice, pharmacological inhibition of EZH2 with GA or GSK126 also improved tubulo-interstitial damage and antagonized activation of Notch signaling. In cultured renal epithelial cells, TGFb1 exposure promoted the interaction of EZH2 with Notch1 or Notch3, and expression of Jagged-1, Hes1 and Hes2, and EZH inhibition abrogated these responses. Finally, chromatin immunoprecipitation indicates that kidney injury enhanced EZH2 and H3K27me3 at the promoter regions of the Notch1 and Notch3 promoter, and treatment with EZH2 inhibitor abolished this response.


Our data indicate that overexpression of EZH2 in renal tubular cells and fibroblasts contributes to renal fibrosis by a mechanism associated with the activation of Notch signaling and suppression of Klotho and BMP7.


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