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Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment

Author

Listed:
  • Juntao Chen

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation)

  • Cuidi Xu

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation)

  • Kun Yang

    (Fudan University, Shanghai Institute of Cardiovascular Diseases)

  • Rifeng Gao

    (Fudan University)

  • Yirui Cao

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation)

  • Lifei Liang

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation)

  • Siyue Chen

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation)

  • Shihao Xu

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation)

  • Ruiming Rong

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation)

  • Jina Wang

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation)

  • Tongyu Zhu

    (Fudan University
    Shanghai Key Laboratory of Organ Transplantation
    Shanghai Medical College Fudan University)

Abstract

Ischemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). The role of N6-methyladenosine (m6A) modification in AKI remains unclear. Here, we characterize the role of AlkB homolog 5 (ALKBH5) and m6A modification in an I/R-induced renal injury model in male mice. Alkbh5-knockout mice exhibit milder pathological damage and better renal function than wild-type mice post-IRI, whereas Alkbh5-knockin mice show contrary results. Also conditional knockout of Alkbh5 in the tubular epithelial cells alleviates I/R-induced AKI and fibrosis. CCL28 is identified as a target of ALKBH5. Furthermore, Ccl28 mRNA stability increases with Alkbh5 deficiency, mediating by the binding of insulin-like growth factor 2 binding protein 2. Treg recruitment is upregulated and inflammatory cells are inhibited by the increased CCL28 level in IRI-Alkbh5fl/flKspCre mice. The ALKBH5 inhibitor IOX1 exhibits protective effects against I/R-induced AKI. In summary, inhibition of ALKBH5 promotes the m6A modifications of Ccl28 mRNA, enhancing its stability, and regulating the Treg/inflammatory cell axis. ALKBH5 and this axis is a potential AKI treatment target.

Suggested Citation

  • Juntao Chen & Cuidi Xu & Kun Yang & Rifeng Gao & Yirui Cao & Lifei Liang & Siyue Chen & Shihao Xu & Ruiming Rong & Jina Wang & Tongyu Zhu, 2023. "Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36747-y
    DOI: 10.1038/s41467-023-36747-y
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    References listed on IDEAS

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    1. Andrea Facciabene & Xiaohui Peng & Ian S. Hagemann & Klara Balint & Andrea Barchetti & Li-Ping Wang & Phyllis A. Gimotty & C. Blake Gilks & Priti Lal & Lin Zhang & George Coukos, 2011. "Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells," Nature, Nature, vol. 475(7355), pages 226-230, July.
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