UBC9-mediated p53 SUMOylation drives tubular senescence and exacerbates acute kidney injury in mice.

The pathogenesis of acute kidney injury (AKI) is closely related to the senescence of renal tubular epithelial cells (RTECs). The role of small ubiquitin-like modification (SUMOylation) in cellular stress and senescence has been gradually elucidated. Recent evidence has demonstrated that SUMOylation of p53 promotes cellular senescence. In this study, we investigated whether p53 SUMOylation-mediated cellular senescence contributes to AKI. A mouse AKI model was established via intraperitoneal injections of cisplatin (20 mg/kg, i.p.). The mice were sacrificed 72 h after the injection, and both blood and kidney tissue were collected. We found that UBC9 (Ube2i), the sole E2-conjugating enzyme for SUMOylation, was significantly upregulated in injured kidneys and drove p53-mediated cellular senescence. Tubular-specific knockdown of Ube2i or administration of the small-molecule UBC9 inhibitor 2-D08 (10 mg/kg, i.p, twice prior to and post-cisplatin injection) markedly alleviated senescence-related marker expression, improved renal function, and attenuated tissue damage in AKI model mice. We demonstrated that UBC9 interacted with p53 and promoted its SUMOylation at lysine 386 (K386). Chromatin immunoprecipitation assays demonstrated that UBC9 enhanced p53 binding to the p21 promoter, whereas the K386R mutation abolished this interaction. These results establish UBC9-mediated p53 SUMOylation as a critical pathway in acute injury-related renal senescence in mice and suggest its potential as a therapeutic target.