Department of Pharmacology, Shandong University School of Medicine, #44, Wenhua Xi Road, Jinan, 250012, Shandong, People's Republic of China.
Department of Nephrology, Shandong Provincial Hospital Affiliated with Shandong University, Jinan, 250021, China.
J Mol Med (Berl). 2018 Jan;96(1):97-109. doi: 10.1007/s00109-017-1606-5. Epub 2017 Nov 7.
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 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 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 normally causes renal fibrosis. Deficiency of β-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 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 pathways may be an innovative therapeutic strategy for treating patients with renal fibrosis.
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.
尽管在理解导致肾纤维化发病机制的机制方面取得了重大进展，但目前临床上只有少数几种疗法可用于治疗或预防肾纤维化。因此，确定肾纤维化发病机制中涉及的关键细胞和分子介质将为治疗慢性肾脏病（CKD）患者提供新的治疗策略。β- arrestin-1 是β- arrestin 家族的一员，不仅是 G 蛋白偶联受体（GPCR）的负衔接蛋白，而且还作为支架蛋白发挥作用，并在 GPCR 激活的情况下调节多种细胞功能。在这项研究中，我们首次发现β- arrestin-1 在单侧输尿管梗阻肾病小鼠的肾脏中以及在糖尿病肾病、多囊肾病或尿脓毒症患者的石蜡包埋肾脏切片中均上调，这通常会导致肾纤维化。在体内和体外研究中，β-arrestin-1 缺陷的小鼠通过调节炎症反应、肾脏成纤维细胞激活和上皮-间充质转化（EMT），显著减轻了肾纤维化。此外，我们发现，在 Wnt 的主要同工型中，Wnt1 受β-arrestin-1 调节，Wnt1 基因沉默抑制了β-catenin 的激活，并抑制了β-arrestin-1 介导的肾纤维化。总之，我们的研究结果表明，β-arrestin-1 是肾纤维化发展中信号转导途径的关键组成部分之一。调节这些途径可能是治疗肾纤维化患者的一种创新治疗策略。
