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

doi:10.1038/s41467-023-36747-y

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

Nat Commun. 2023 Mar 1;14(1):1161. doi: 10.1038/s41467-023-36747-y.

Authors

Juntao Chen^#^{1

2}, Cuidi Xu^#^{1

2}, Kun Yang^#³, Rifeng Gao⁴, Yirui Cao^{1

2}, Lifei Liang^{1

2}, Siyue Chen^{1

2}, Shihao Xu^{1

2}, Ruiming Rong^{5

6}, Jina Wang^{7

8}, Tongyu Zhu^{9

10

11}

Affiliations

¹ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
³ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
⁴ The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
⁵ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China. rong.ruiming@zs-hospital.sh.cn.
⁶ Shanghai Key Laboratory of Organ Transplantation, Shanghai, China. rong.ruiming@zs-hospital.sh.cn.
⁷ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China. wang.jina@zs-hospital.sh.cn.
⁸ Shanghai Key Laboratory of Organ Transplantation, Shanghai, China. wang.jina@zs-hospital.sh.cn.
⁹ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China. zhu.tongyu@zs-hospital.sh.cn.
¹⁰ Shanghai Key Laboratory of Organ Transplantation, Shanghai, China. zhu.tongyu@zs-hospital.sh.cn.
¹¹ Shanghai Medical College Fudan University, Shanghai, China. zhu.tongyu@zs-hospital.sh.cn.

^# Contributed equally.

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/flKsp^Cre 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury*
AlkB Homolog 5, RNA Demethylase* / genetics
Animals
Chemokines, CC*
Kidney / physiology
Male
Mice
Mice, Knockout
T-Lymphocytes, Regulatory*

Substances

Ccl28 protein, mouse
Chemokines, CC
ALKBH5 protein, mouse
AlkB Homolog 5, RNA Demethylase