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Kidney Week

Abstract: PO0592

EZH2 Mediates Renal Fibrosis and Links Activation of Notch Signaling and Suppression of Klotho and BMP-7 Expression

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Author

  • Zhuang, Shougang, Rhode Isand Hospital, Brown University, Providence, Rhode Island, United States

Group or Team Name

  • Shanghai East Hospital, Shanghai, China
Background

Our previous studies have shown that pharmacological blocking EZH2 (Enhancer of Zeste Homolog 2), a histone H3 lysine 27 methyltranferse, attenuates renal fibrosis in a murine model of renal fibrosis, but the underlying mechanism in this process remain undefined.

Methods

In this study, we used two highly selective EZH2 inhibitors and conditional knockout mice to evaluate the effect of EZH2 inhibition on renal fibrosis and activation of profibrotic signaling pathways and expression of renoprotective proteins in two murine models of chronic kidney disease (CKD) induced by UUO and 5/6 nephrectomy (SNx).

Results

Global inhibition of EZH2 by administration of gambogic acid or GSK-126 and conditional depletion of EZH2 in pericytes suppressed renal fibroblast activation and fibrogenesis in the kidney with UUO and SNx. Treatment with these inhibitors or EZH2 siRNA also inhibited serum- and TGF-β1-induced activation of renal fibroblasts in culture. Moreover, pharmacological and genetic inhibition of EZH2 suppressed expression of Notch-1, Notch-3, Jagged-1 and HES-1 and HEY-2 in vivo and in vitro. Similarly, inhibition of EZH2 was effective in inhibiting phosphorylation of extracellular signal-regulated kinase 1/2, AKT and NF-kB as well as expression of multiple profibrogenic cytokines/chemokines and renal macrophage infiltration. In contrast, EZH2 inhibitors prevented injury-induced downregulation of Klotho and BMP-7, two anti-fibrotic proteins in the kidney.

Conclusion

These results revealed that EZH2 may promote renal fibrosis and activation of renal fibroblasts by activation of Notch signaling, downregulation of Klotho and BMP-7 and induction of inflammation in the injured kidney. Targeting EZH2 may be a novel therapeutic strategy to treat CKD.

Funding

  • NIDDK Support