Ubiquitin-Specific Protease 11 Promotes Uric Acid-Induced Renal Tubular Epithelial Cell Apoptosis via Deubiquitinating P53 and Enhancing Mitochondrial Outer Membrane Permeabilization.

Background/

Objectives

Chronic kidney disease (CKD) has emerged as a critical global health challenge, driven by its high prevalence and poor prognosis. Ubiquitin-specific protease 11 (USP11), a deubiquitinating enzyme, participates in DNA damage repair, cell-cycle regulation, and immune modulation, and has been shown to promote epithelial-mesenchymal transition in renal tubular epithelial cells (TECs) during CKD progression. However, whether USP11 also plays a critical role in the apoptosis of TECs remains to be elucidated.

Methods

In this study, we demonstrate that USP11 deubiquitinates and stabilizes p53, thereby activating the p53-mediated canonical mitochondrial pathway of apoptosis in cultured human proximal TECs (HK-2).

Results

In uric acid (UA)-stimulated HK-2 cells, activated p53 subsequently increases mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c from the mitochondria into the cytosol, which, in turn, activates caspase 9 and caspase 3, and ultimately promotes TEC apoptosis. Inhibition of USP11 with siRNA transfection or mitoxantrone (MTX), a small-molecule inhibitor of USP11, downregulates p53 expression and blocks cytochrome c release into the cytosol, thereby significantly reducing TEC apoptosis. In vivo, both conditional genetic knockout and pharmacological inhibition of USP11 effectively reduce apoptosis of tubular cells and ameliorate kidney injury in a mouse CKD model of hyperuricemic nephropathy (HN).

Conclusions

In summary, our results underscore the pivotal role of USP11 in TEC apoptosis during CKD progression and suggest that targeting USP11 represents a potential therapeutic approach for CKD patients.