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Inhibition of USP4 attenuates epithelial-mesenchymal transition of renal tubular epithelial cells by TβRI

By Jinyun Pu, Lixia Wang, Jie Wang, Yu Zhang, Jianhua Zhou

Posted 28 Oct 2020
bioRxiv DOI: 10.1101/2020.10.28.358796

The process of epithelial-mesenchymal transition (EMT) is required for the progression of renal interstitial fibrosis (RIF). Ubiquitin-specific protease 4 (USP4) can facilitate development of transforming growth factor, beta 1 (TGF-{beta}1) induced EMT in some cancer cells. However, the role of USP4 in EMT during RIF remains unknown. We aimed to explore the effect of USP4 on the EMT induced by TGF-{beta}1 of renal tubular epithelial cells and involved mechanism in RIF. In vivo, on the 7th and 14th day after unilateral ureteral obstruction (UUO), the expression of USP4 protein in the obstructed kidneys was detected by immunohistochemistry and Western blot assay. In vitro, NRK-52E cells were stimulated with TGF-{beta}1 10ng/ml. The protein expressions of USP4, E-cadherin and alpha smooth muscle actin (-SMA) were detected at different time points by Western blot. After transfected with USP4 siRNA, the cells were cultured with TGF-{beta}1 for additional 24 hours. The expressions of E-cadherin, -SMA, and TGF{beta} receptor type I (T{beta}RI) were detected by immunofluorescence. And the protein expressions of USP4, E-cadherin, -SMA and T{beta}RI were detected by Western blot assay. Compared with sham operation group, the expression of USP4 in UUO model group increased significantly with the prolongation of obstruction time. After NRK-52E was stimulated by TGF-{beta}1, the expression of USP4 protein increased gradually. At 6h, 12h, and 24h, the difference between the experimental group and the control group was statistically significant. At the same time, E-cadherin decreased significantly, while -SMA increased significantly. Compared with the TGF-{beta}1 group, the cells in USP4 siRNA transfection group restored E-cadherin and weakened -SMA expression. At the same time, protein expressions of USP4 and T{beta}RI were also significantly decreased. These data imply that USP4 is a harmful molecule induced by TGF-{beta}1, which plays an important role by upregulating the expression of T{beta}RI and promoting EMT of renal tubular epithelial cells, thereby facilitating renal interstitial fibrosis.

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