Research Paper Volume 14, Issue 18 pp 7527—7546

Ubiquitin-like protein FAT10 promotes renal fibrosis by stabilizing USP7 to prolong CHK1-mediated G2/M arrest in renal tubular epithelial cells

Ying Shao1, *, , Wenming Zhang2,3, , Dongnian Du2,3, , Yi Yu4, , Qing Li5, , Xiaogang Peng3, *, ,

  • 1 Queen Mary School, Nanchang University Jiangxi Medical College, Nanchang 330006, Jiangxi Province, China
  • 2 Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
  • 3 Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
  • 4 Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
  • 5 Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
* Equal contribution

Received: January 30, 2022       Accepted: September 5, 2022       Published: September 22, 2022      

https://doi.org/10.18632/aging.204301
How to Cite

Copyright: © 2022 Shao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Renal fibrosis is the pathological hallmark of chronic kidney disease that is influenced by numerous factors. Arrest of renal tubular epithelial cells (RTECs) in G2/M phase is closely correlated with the progression of renal fibrosis; however, the mechanisms mediating these responses remain poorly defined. In this study, we observed that human leukocyte antigen-F adjacent transcript 10 (FAT10) deficiency abolished hypoxia-induced upregulation of checkpoint kinase 1 (CHK1) expression in RTECs derived from FAT10+/+ and FAT10−/− mice. Further investigations revealed that FAT10 contributes to CHK1-mediated G2/M arrest and production of pro-fibrotic cytokines in RTECs exposed to hypoxia. Mechanistically, FAT10 directly interacted with and stabilized the deubiquitylating enzyme ubiquitin specific protease 7 (USP7) to mediate CHK1 upregulation, thereby promoting CHK1-mediated G2/M arrest in RTECs. In animal model, FAT10 expression was upregulated in the obstructed kidneys of mice induced by unilateral ureteric obstruction injury, and FAT10−/− mice exhibited reduced unilateral ureteric obstruction injury induced-renal fibrosis compared with FAT10+/+ mice. Furthermore, in a cohort of patients with calculi-related chronic kidney disease, upregulated FAT10 expression was positively correlated with renal fibrosis and the USP7/CHK1 axis. These novel findings indicate that FAT10 prolongs CHK1-mediated G2/M arrest via USP7 to promote renal fibrosis, and inhibition of the FAT10/USP7/CHK1 axis might be a plausible therapeutic approach to alleviate renal fibrosis in chronic kidney disease.

Abbreviations

RTECs: renal tubular epithelial cells; FAT10: human leukocyte antigen-F adjacent transcript 10; CHK1: checkpoint kinase 1; USP7: ubiquitin specific protease 7; CDKN1A: cyclin dependent kinase inhibitor 1A; CKD: chronic kidney disease; ECM: extracellular matrix; UPS: ubiquitin-proteasome pathway; UUO: unilateral ureteric obstruction; TIF: tubulointerstitial fibrosis; LC–MS/MS: Liquid chromatography with tandem mass spectrometry; qRT–PCR: quantitative real-time PCR; CHX: cycloheximide; IHC: Immunohistochemistry; Immunofluorescence: IF; Co-IP: Co-immunoprecipitation.