beta-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/beta-catenin signaling in mice

Despite substantial progress being made in understanding the mechanisms contributing to the pathogenesis of renal fibrosis, there are only a few therapies available to treat or prevent renal fibrosis in clinical use today. Therefore, identifying the key cellular and molecular mediators involved in the pathogenesis of renal fibrosis will provide new therapeutic strategy for treating patients with chronic kidney disease (CKD). beta-Arrestin-1, a member of beta-arrestin family, not only is a negative adaptor of G protein-coupled receptors (GPCRs), but also acts as a scaffold protein and regulates a diverse array of cellular functions independent of GPCR activation. In this study, we identified for the first time that beta-arrestin-1 was upregulated in the kidney from mice with unilateral ureteral obstruction nephropathy as well as in the paraffin-embedded sections of human kidneys from the patients with diabetic nephropathy, polycystic kidney, or uronephrosis, which normally causes renal fibrosis. Deficiency of beta-arrestin-1 in mice significantly alleviated renal fibrosis by the regulation of inflammatory responses, kidney fibroblast activation, and epithelial-mesenchymal transition (EMT) in both in vivo and in vitro studies. Furthermore, we found that among the major isoforms of Wnts, Wnt1 was regulated by beta-arrestin-1 and gene silencing of Wnt1 inhibited the activation of beta-catenin and suppressed beta-arrestin-1-mediated renal fibrosis. Collectively, our results indicate that beta-arrestin-1 is one of the critical components of signal transduction pathways in the development of renal fibrosis. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with renal fibrosis.