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

Juntao Chen, Cuidi Xu, Kun Yang, Rifeng Gao, Yirui Cao, Lifei Liang, Siyue Chen, Shihao Xu, Ruiming Rong (), Jina Wang () and Tongyu Zhu ()
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Juntao Chen: Fudan University
Cuidi Xu: Fudan University
Kun Yang: Fudan University, Shanghai Institute of Cardiovascular Diseases
Rifeng Gao: Fudan University
Yirui Cao: Fudan University
Lifei Liang: Fudan University
Siyue Chen: Fudan University
Shihao Xu: Fudan University
Ruiming Rong: Fudan University
Jina Wang: Fudan University
Tongyu Zhu: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36747-y

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