USP22 aggravated diabetic renal tubulointerstitial fibrosis progression through deubiquitinating and stabilizing Snail1

Renal tubulointerstitial fibrosis (TIF) is one of the main pathological changes induced by diabetic kidney disease (DKD), and epithelial-to-mesenchymal transition (EMT) induced by high glucose (HG) can promote TIF. Our previous study has shown that ubiquitin-specific protease 22 (USP22) could affect the process of DKD by deubiquitinating and stabilizing Sirt1 in glomerular mesangial cells. However, whether USP22 could regulate EMT occurrence in renal tubular epithelial cells and further aggravate the pathological process of TIF in DKD remains to be elucidated. In this study, we found that USP22 expression was upregulated in kidney tissues of db/db mice and HG-treated NRK-52E cells. In vitro, USP22 overexpression promoted the EMT process of NRK-52E cells stimulated by HG and further increased the levels of extracellular matrix (ECM) components such as fibronectin, Collagen I, and Collagen Ⅳ. Meanwhile, USP22 deficiency exhibited the opposite effects. Mechanism studies showed that USP22, depending on its deubiquitinase activity, deubiquitinated and stabilized the EMT transcriptional factor Snail1. In vivo experiment showed that interfering with USP22 could improve the renal pathological damages and renal function of the db/db spontaneous diabetic mice by decreasing Snail1 expression, which could inhibit EMT occurrence, and reduce the production of ECM components. These results suggested that USP22 could accelerate renal EMT and promote the pathological progression of diabetic TIF by deubiquitinating Snail1, providing an experimental basis for using USP22 as a potential target for DKD.