NAT10 Promotes Tubular Epithelial Cell Senescence in Cisplatin-Induced Acute Kidney Injury by Regulating DDX17
Acute kidney injury (AKI) is a severe clinical syndrome with high morbidity and mortality, yet its pathogenesis remains incompletely understood, and effective therapeutic strategies are still lacking. In this study, we observed significant upregulation of N-acetyltransferase 10 (NAT10) in the tubular epithelial cells of Cisplatin-induced AKI. Lentivirus-mediated knockdown of NAT10 or treatment with NAT10 inhibitor Remodelin, ameliorated Cisplatin-induced renal dysfunction and tubular injury. Importantly, NAT10 inhibition markedly attenuated cellular senescence in Cisplatin-induced AKI, as evidenced by reduced senescence-associated ß-galactosidase (SA-ß-gal) activity, downregulation of senescence markers (p53, p21, and ?-H2A.X), and decreased levels of senescence-associated secretory phenotype (SASP) factors (IL-1ß, IL-6, and TNF-a). Mechanistically, co-immunoprecipitation assay suggested that NAT10 interacted with DDX17 to regulate its expression. Knockdown or inhibition of NAT10 reduced the protein expression of DDX17 in Cisplatin-injured kidneys. While silencing DDX17 could inhibit Cisplatin-induced senescence in HK-2 cells. Furthermore, we demonstrated that the effects of NAT10 on Cisplatin-induced tubular injury and senescence was dependent on DDX17. Our study revealed a novel mechanism by which NAT10 promoted Cisplatin-induced renal tubular cell senescence via DDX17 upregulation, suggesting that targeting the NAT10/DDX17 signaling axis may offer a potential therapeutic strategy for AKI. Overall design: Cisplatin-induced HK-2 cells transfected with either negative control siRNA or NAT10 siRNA