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Abstract: PO0353

Targeting Polycomb Repressive Complex 2 Protects Against Cisplatin-Induced AKI in Mice

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Tingting, Shanghai East Hospital, Shanghai, Shanghai, China
  • Yu, Chao, Shanghai East Hospital, Shanghai, Shanghai, China
  • Zhuang, Shougang, Rhode Island Hospital, Providence, Rhode Island, United States
Background

Our previous studies have shown that blocking EZH2 (Enhancer of Zeste Homolog 2), a catalyzing subunit of polycomb repressive complex 2 (PRC2) with histone methyltransferase activity, protects against acute kidney injury (AKI). The role and mechanism of the entire PRC2 in AKI remain undefined. In this study, we investigated the involvement of PRC2 in the pathogenesis of AKI following cisplatin exposure.

Methods

A potent and selective PRC2 inhibitor EED226 was used to evaluate the effect of loss of PRC2 catalytic activity on renal function and tubular cell injury as well as activation of key apoptotic signaling pathways and expression of renoprotective proteins in a murine model of cisplatin-induced AKI.

Results

Administration of EED226 improved renal function, attenuated renal pathological changes, and reduced renal tubule injury and apoptosis in a murine model of cisplatin-induced AKI. In cultured renal epithelial cells, treatment with either EED226 or EED siRNA also reduced apoptosis. Mechanistically, EED226 treatment inhibited cisplatin-induced phosphorylation of p53 and fox3a, two transcriptional factors associated with apoptosis, and prevented downregulation of expression of Sirt3 and PGC-1α, two proteins that contribute to mitochondrial protection. Moreover, EED226 also enhanced renal tubular cell proliferation and suppressed inflammatory responses and phosphorylation of STAT3 and NF-κB, two transcriptional factors associated with inflammation.

Conclusion

These results indicate that targeted inhibition of PRC2 can improve renal function and promote the survival and proliferation of renal tubular cells through mechanisms associated with inhibition of p53 and fox3a signaling pathways and preserved expression of Sirt3 and PGC-1α.

Funding

  • Government Support – Non-U.S.