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Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence

Author

Listed:
  • Lingzhi Li

    (West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases)

  • Ting Xiang

    (West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases)

  • Jingjing Guo

    (West China Hospital of Sichuan University)

  • Fan Guo

    (West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases)

  • Yiting Wu

    (West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases)

  • Han Feng

    (Tulane University School of Medicine)

  • Jing Liu

    (West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases)

  • Sibei Tao

    (West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases)

  • Ping Fu

    (West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases)

  • Liang Ma

    (West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases)

Abstract

Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1β expression, which thereby alleviate IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.

Suggested Citation

  • Lingzhi Li & Ting Xiang & Jingjing Guo & Fan Guo & Yiting Wu & Han Feng & Jing Liu & Sibei Tao & Ping Fu & Liang Ma, 2024. "Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47315-3
    DOI: 10.1038/s41467-024-47315-3
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