Silencing of USP22 promotes FGF11 degradation to attenuates renal fibrosis in diabetic kidney disease

Diabetic kidney disease (DKD) is a major cause of end-stage renal disease that is characterized by renal fibrosis. Fibroblast Growth Factor 11 (FGF11) is reported to be involved in mesangial cell fibrosis; however, its mechanism is not fully understood. This study aimed to investigate the role of FGF11 and its ubiquitination regulatory mechanism mediated by Ubiquitin-Specific Protease 22 (USP22) in DKD. SV40 MES 13 cells were treated with high glucose (HG).

A DKD mouse model was established using streptozotocin injection and high-fat diet feeding (6 mice/group). FGF11 mRNA and protein levels in cells and kidneys of mice were detected using qPCR and immunoblotting. Cell proliferation was evaluated using cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assay, and fibrosis was evaluated using immunoblotting. The regulation of USP22 on FGF11 ubiquitination was analyzed using immunoprecipitation and immunoblotting. Renal injury was assessed by measuring histological fibrosis and injury markers.

FGF11 was highly expressed in the kidneys of DKD mice and HG-treated cells. Knockdown of FGF11 inhibited HG-induced proliferation and fibrosis. Furthermore, we discovered that USP22 knockdown promoted FGF11 degradation by enhancing its K48-linked ubiquitination, thus reducing FGF11 stability. Overexpression of FGF11 reversed the inhibition of proliferation and fibrosis caused by USP22 silence. In vivo, USP22 knockdown alleviated renal injury and fibrosis in DKD mice via decreasing FGF11 expression.

Silencing of USP22 inhibits mesangial cell proliferation and fibrosis by promoting the ubiquitination of FGF11, which is related to the alleviation of DKD, suggesting that targeting the USP22-FGF11 axis may provide a therapeutic strategy for DKD.