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, Tongyu Zhu
Abstract
Abstract Ischemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). The role of N 6- 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- Alkbh5 fl/fl Ksp Cre mice. The ALKBH5 inhibitor IOX1 exhibits protective effects against I/R-induced AKI. In summary, inhibition of ALKBH5 promotes the m6A modifications of Ccl 28 mRNA, enhancing its stability, and regulating the Treg/inflammatory cell axis. ALKBH5 and this axis is a potential AKI treatment target.