FBF1 Deficiency Protects against Chronic Progression of Cisplatin-Induced AKI

Le résumé fourni par la source

Background: Cisplatin-induced nephrotoxicity exhibits hallmarks of acute kidney injury (AKI), yest its long-term exposure results in chronic kidney disease (CKD). Recent evidence shows that senescence of renal epithelial cells contributes to chronic progression after injury. However, how senescence is initiated in the injured kidneys remains poorly defined. Methods: C57BL/6 mice were exposed to repeated low-dose cisplatin (RLDC) treatment consisting of 4 weekly injections of 8 mg/kg cisplatin. Mouse proximal tubular (BUMPT) cells were exposed to 4 cycles of 2 μΜ cisplatin treatment, with 7-hour cisplatin exposure followed by 17-hour cisplatin-free culture medium incubation. The level of cellular senescence was determined by measuring Senescent Associated (SA)-b-Gal staining, and levels of senescence markers as well as inflammatory Senescence-Associated Secretory Phenotype (SASP) markers. Fbf1 deficiency in mice were established by homozygous Fbf1tm1a/tm1a mutant using the ‘‘knockout first strategy’’. FBF1 knockdown BUMPT cell lines were generated by using shRNA. Western blotting, confocal imaging were used to determine the expression and subcellular localization of key components. Histological/immunofluorescent stain, serum BUN, and creatinine level were detected to investigate the progression of kidney injury. Immunoprecipitation or chromatin immunoprecipitation assay were performed to analyze protein-protein or protein-DNA interaction. Results: We discover that RLDC treatment of C57BL/6 mice induced FBF1 upregulation in injured kidney tubules, which develop characteristics of cellular senescence. RLDC prompted FBF1 nuclear translocation to initiate senescence in Cisplatin-exposed BUMPT cells. FBF1 depletion effectively reduce senescent burden of BUMPT cells, reversed the profibrotic phenotype, and increased regenerative capacity following RLDC treatment. Consistently, deficiency of FBF1 in vivo suppressed senescence initiation, attenuated renal fibrosis and improved tubular repair. Mechanistically, we discovered that nuclear-translocated FBF1 triggered the recruitment of transcriptional factor HNF-1β to promyelocytic leukemia nuclear bodies (PML-NBs) to regulate senescence responses in damaged cells. Conclusion: Suppression of the FBF1 pathway ameliorates adverse senescence-associated impacts and prevents AKI-CKD transition in cisplatin-treated kidneys. Funding: NIDDK Support

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.