NSUN3 Aggravates Sepsis‐Associated Acute Kidney Injury by Stabilising TIFA mRNA Through m5C

ABSTRACT Background Acute kidney injury (AKI) is a common complication of sepsis and also a risk factor for progression of chronic kidney disease. NOP2/Sun RNA methyltransferase 3 (NSUN3) is involved in the regulation of sepsis progression. However, the mechanism by which NSUN3 regulates sepsis‐associated AKI (SA‐AKI) remains unclear. Methods SA‐AKI mouse model and lipopolysaccharide (LPS)‐induced injury model in HK‐2 cells were constructed. Haematoxylin–eosin staining, quantitative polymerase chain reaction (qPCR), western blotting, cell counting kit 8, flow cytometry, 2′,7′‐dichlorofluorescein diacetate, enzyme‐linked immunosorbent assay, methylation RNA immunoprecipitation‐qPCR, actinomycin D and TdT‐mediated dUTP Nick‐End Labelling staining assays were utilised to explore the expression and related mechanism of NSUN3 in the SA‐AKI models. Results The expression of NSUN3 and tumour necrosis factor receptor‐associated factor (TRAF)‐interacting protein with forkhead‐associated domain (TIFA) was upregulated in mice with SA‐AKI and LPS‐induced HK‐2 cells. Knockdown of NSUN3 inhibited LPS‐induced injury in HK‐2 cells. Mechanically, NSUN3 increased TIFA mRNA stability and upregulated its expression through m5C modification. Moreover, knockdown of NSUN3 was found to alleviate LPS‐induced HK‐2 cell injury and SA‐AKI in mice by reducing TIFA expression. Conclusion NSUN3 aggravates SA‐AKI by stabilising TIFA mRNA through m5C, indicating that NSUN3 may be a biomarker for SA‐AKI.