Ubiquitin-specific protease 11 facilitates the activation and proliferation of renal interstitial fibroblasts through epidermal growth factor receptor signaling pathways.

Chronic kidney disease is a worldwide health problem, and its incidence is on the rise. It has previously been shown that ubiquitin-specific protease 11 (USP11) promotes partial epithelial-to-mesenchymal transition in uric acid-stimulated tubular epithelial cells during renal fibrosis. However, its specific function and mechanism in renal interstitial fibroblasts is still unknown. In this study, we found that uric acid could also upregulate the USP11 levels in cultured fibroblasts (NRK-49F) under dose gradient and time gradient, with an approximately 3-4 fold increase. Genetic and pharmacological depletion of USP11 blocked activation of renal interstitial fibroblasts leading to an approximately 70-90% reduction in α-SMA and collagen I expressions. USP11 increased the phosphorylation level of epidermal growth factor receptor, thereby activating its downstream signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/protein kinase B and mitogen-activated protein kinase /extracellular regulated protein kinases, which further activated nuclear transcription factors, Snail and Slug. Moreover, USP11 could also affect the proliferation and migration of NRK49F, by upregulating the expression levels of proliferating cell nuclear antigen and cyclin E. Thus, our study offers comprehensive evidence that USP11 is a promising target for kidney fibrosis and that inhibiting USP11 could be an effective strategy for treating chronic kideny disease.