ORIGINAL ARTICLE β-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/β-catenin signaling in mice Huiyan Xu 1,2 & Quanxin Li 1 & Jiang Liu 1 & Jiaqing Zhu 1 & Liang Li 1 & Ziying Wang 1 & Yan Zhang 1 & Yu Sun 1 & Jinpeng Sun 3 & Rong Wang 2 & Fan Yi 1,4 Received: 25 June 2017 /Revised: 13 October 2017 /Accepted: 25 October 2017 # Springer-Verlag GmbH Germany 2017 Abstract 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). β- Arrestin-1, a member of β-arrestin family, not only is a neg- ative 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 β-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 nor- mally causes renal fibrosis. Deficiency of β-arrestin-1 in mice significantly alleviated renal fibrosis by the regulation of in- flammatory 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 β-arrestin-1 and gene silencing of Wnt1 inhibited the activation of β-catenin and suppressed β-arrestin-1-mediated renal fibrosis. Collectively, our results indicate that β-arrestin-1 is one of the critical components of signal transduction pathways in the development of renal fibrosis. Modulation of these path- ways may be an innovative therapeutic strategy for treating patients with renal fibrosis. Key messages & β-Arrestin-1 was upregulated in the kidney from mice with UUO nephropathy. & β-Arrestin-1 regulated kidney fibroblast activation and epithelial-mesenchymal transition. & β-Arrestin-1 exacerbated renal fibrosis via mediating Wnt1/β-catenin signaling. Keywords Renal fibrosis . G protein-coupled receptors . β-Arrestin . Wnt/β-catenin signaling Introduction Renal tubulointerstitial fibrosis is a crucial determinant under- lying the progression from chronic kidney disease (CKD) to end-stage renal disease (ESRD) [1, 2]. Despite substantial progress being made in understanding the mechanisms con- tributing to the pathogenesis of renal fibrosis, such as fibro- blast accumulation, epithelial-to-mesenchymal transition (EMT), infiltration of inflammatory cells, tubular cell loss, and rarefaction of the peritubular microvasculature [1], there is only a few therapy 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 * Fan Yi fanyi@sdu.edu.cn 1 Department of Pharmacology, Shandong University School of Medicine, #44, Wenhua Xi Road, Jinan 250012, Shandong, People’ s Republic of China 2 Department of Nephrology, Shandong Provincial Hospital Affiliated with Shandong University, Jinan 250021, China 3 Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan 250012, China 4 The State Key Laboratory of Microbial Technology, Shandong University, Jinan 250100, China J Mol Med https://doi.org/10.1007/s00109-017-1606-5