Inhibition of Ubiquitin-specific Protease 4 Attenuates Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells via Transforming Growth Factor Beta Receptor Type I.

Abstract

Ubiquitin-specific protease 4 (USP4) facilitates the development of transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in various cancer cells. Moreover, EMT of renal tubular epithelial cells (RTECs) is required for the progression of renal interstitial fibrosis. However, the role of USP4 in EMT of RTECs remains unknown. The present study aimed to explore the effect of USP4 on the EMT of RTECs as well as the involved mechanism. In established unilateral ureteral obstruction (UUO) rats and NRK-52E cells, immunohistochemistry and Western blot assays were performed. USP4 expression was increased significantly with obstruction time. In NRK-52E cells stimulated by TGF-β1, USP4 expression was increased in a time-dependent manner. In addition, USP4 silencing with specific siRNA indicated that USP4 protein was suppressed effectively. Meanwhile, USP4 siRNA treatment restored E-cadherin and weakened alpha smooth muscle actin (α-SMA) expression, indicating that USP4 may promote EMT. After treatment with USP4 siRNA and TGF-β1 for 24 h, the expression of TGF-β1 receptor type I (TβRI) was decreased. USP4 promotes the EMT of RTECs through upregulating TβRI, thereby facilitating renal interstitial fibrosis. These findings may provide a potential target of USP4 in the treatment of renal fibrosis.