Ubiquitin-specific protease 11 promotes tubular cell senescence via inhibiting p53 ubiquitin degradation during renal fibrosis.

Abstract

Emerging evidence has established that renal tubular epithelial cell (TEC) senescence is an essential driver of renal fibrosis, while the activation of p53/p21 pathway plays a key role in initiating TEC senescence. However, the upstream regulatory mechanisms of p53/p21 pathway activation remain unclear, hindering the development of targeted anti-fibrotic therapies for chronic kidney disease (CKD). This study aimed to reveal the upstream regulator of the p53/p21 pathway and investigate its role in renal fibrosis. Here, we report that unilateral ureteral ligation (UUO) and folic acid (FA)-induced fibrotic mouse kidneys exhibited a marked senescent phenotype and activated p53/p21 pathway, accompanied by significant upregulation of ubiquitin-specific protease 11 (USP11). These changes were further verified in angiotensin II (Ang II)-stimulated HK-2 cells. Both Usp11 knockout and pharmacological inhibition with mitoxantrone (MTX) significantly alleviated UUO-induced p53/p21 pathway activation, tubular senescence and renal fibrosis. Mechanistically, USP11 directly interacted with p53 and protected it from ubiquitin-dependent degradation, thereby promoting tubular cell senescence and fibrosis. Furthermore, we identified Krüppel-like factor 4 (KLF4) as the upstream transcription factor that directly bound to the USP11 promoter and enhanced its transcription under pathological conditions. Our findings demonstrate that the KLF4-USP11-p53 axis drives tubular senescence and renal fibrosis, representing a highly promising therapeutic target for CKD.