Kidney Week

Abstract: SA-PO102

FBF1 Deficiency Protects against Chronic Progression of Cisplatin-Induced AKI

Session Information

• AKI: Inflammation and Cell Cycle
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Robichaud, Jielu Hao, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Jielu Hao Robichaud, MD, PhD

• Chen, Chuan, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Chuan Chen, PhD

• He, Kai, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Kai He, PhD

• Sun, Xiaobo, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Xiaobo Sun

• Dong, Zheng, Augusta University, Augusta, Georgia, United States

Zheng Dong, PhD, FASN

• Hu, Jinghua, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Jinghua Hu, PhD

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 Fbf1^tm1a/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