Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment.
Nat Commun
; 14(1): 1161, 2023 03 01.
Article
in En
| MEDLINE
| ID: mdl-36859428
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes, Regulatory
/
Chemokines, CC
/
Acute Kidney Injury
/
AlkB Homolog 5, RNA Demethylase
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2023
Document type:
Article
Affiliation country: