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Selective EZH2 inhibitor zld1039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway

Acta Pharmacologica Sinica volume 43, pages 2067–2080 (2022)Cite this article

Abstract

Enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), is a histone lysine methyltransferase mediating trimethylation of histone H3 at lysine 27 (H3K27me3), which is a repressive marker at the transcriptional level. EZH2 sustains normal renal function and its overexpression has bad properties. Inhibition of EZH2 overexpression exerts protective effect against acute kidney injury (AKI). A small-molecule compound zld1039 has been developed as an efficient and selective EZH2 inhibitor. In this study, we evaluated the efficacy of zld1039 in the treatment of cisplatin-induced AKI in mice. Before injection of cisplatin (20 mg/kg, i.p.), mice were administered zld1039 (100, 200 mg/kg, i.g.) once, then in the following 3 days. We found that cisplatin-treated mice displayed serious AKI symptoms, evidenced by kidney dysfunction and kidney histological injury, accompanied by EZH2 upregulation in the nucleus of renal tubular epithelial cells. Administration of zld1039 dose-dependently alleviated renal dysfunction as well as the histological injury, inflammation and cell apoptosis in cisplatin-treated mice. We revealed that zld1039 administration exerted an anti-inflammatory effect in kidney of cisplatin-treated mice via H3K27me3 inhibition, raf kinase inhibitor protein (RKIP) upregulation and NF-κB p65 repression. In the cisplatin-treated mouse renal tubular epithelial (TCMK-1) cells, silencing of RKIP with siRNA did not abolish the anti-inflammatory effect of EZH2 inhibition, suggesting that RKIP was partially involved in the anti-inflammatory effect of zld1039. Collectively, EZH2 inhibition alleviates inflammation in cisplatin-induced mouse AKI via upregulating RKIP and blocking NF-κB p65 signaling in cisplatin-induced AKI. The potent and selective EZH2 inhibitor zld1039 has the potential as a promising agent for the treatment of AKI.

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Fig. 1: EZH2 inhibition by zld1039 protected renal dysfunction and alleviated histologic damage in cisplatin-induced AKI mice.
Fig. 2: EZH2 inhibition by zld1039 attenuated renal inflammation and cell apoptosis in cisplatin-induced AKI mice.
Fig. 3: EZH2 inhibition by zld1039 suppressed H3K27me3 expression in cisplatin-induced AKI mice.
Fig. 4: EZH2 inhibition by zld1039 blocked NF-κB signaling activation in cisplatin-induced AKI mice.
Fig. 5: EZH2 inhibition by zld1039 preserved the expression of RKIP in cisplatin-induced AKI mice.
Fig. 6: EZH2 inhibition by zld1039 alleviated cisplatin-induced mouse renal tubular epithelial cells apoptosis and inflammation.
Fig. 7: EZH2 inhibition by zld1039 alleviated cisplatin-induced mouse renal tubular epithelial cells apoptosis and inflammation.
Fig. 8: EZH2 inhibition by zld1039 inhibited cisplatin-induced tubular cell apoptosis and inflammation by H3K27me3-dependent manner.
Fig. 9: EZH2 inhibition by zld1039 preserved RKIP expression and inhibited the activation of NF-κB signaling in cisplatin-stimulated TCMK-1 cells.
Fig. 10: Effect of RKIP knockdown on inflammation in cisplatin-stimulated TCMK-1 cells.

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Acknowledgements

This study was supported by the National Key R&D Program of China (2020YFC2005000), the National Natural Science Foundation of China (82070711), the Science/Technology Project of Sichuan province (2020YFQ0055), and the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University (ZYGD18027).

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Authors and Affiliations

  1. Kidney Research Institute, National Clinical Research Center for Geriatrics and Division of Nephrology, West China Hospital of Sichuan University, Chengdu, 610041, China

    Li Wen, Shao-hua Tao, Fan Guo, Ling-zhi Li, Hong-liu Yang, Liang Ma & Ping Fu

  2. Research Core Facility of West China Hospital, Chengdu, 610041, China

    Yan Liang

  3. Laboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, 610041, China

    Li-dan Zhang

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Contributions

LW, LDZ, and LM designed research, analyzed data, and drafted the article; FG, SHT, and PF contributed new reagents or analytic tools; LZL analyzed and interpretated data; HLY performed research; YL analyzed data; All authors finally approved the version to be published.

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Correspondence to Li-dan Zhang or Liang Ma.

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Wen, L., Tao, Sh., Guo, F. et al. Selective EZH2 inhibitor zld1039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway. Acta Pharmacol Sin 43, 2067–2080 (2022). https://doi.org/10.1038/s41401-021-00837-8

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  • DOI: https://doi.org/10.1038/s41401-021-00837-8

Keywords

  • acute kidney injury
  • inflammation
  • enhancer of zeste homolog 2
  • Raf kinase inhibitor protein
  • NF-κB p65
  • zld1039

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