β-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy.
β-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy.
复制标题
β-抑制蛋白通过抑制糖尿病肾病的自噬来促进足细胞损伤。
DOI：
10.1038/cddis.2016.89
复制
发表时间：
2016-04-07
影响因子：
9
通讯作者：
Yi F
中科院分区：
文献类型：
--
作者：
Liu J;Li QX;Wang XJ;Zhang C;Duan YQ;Wang ZY;Zhang Y;Yu X;Li NJ;Sun JP;Yi F
β-Arrestins是一种多功能蛋白质，最初被鉴定为G蛋白偶联受体（GPCR）的负衔接子。新出现的证据也表明，β-抑制蛋白可以激活信号转导途径，而不依赖于GPCR激活。本研究旨在阐明β-arrestins在糖尿病肾病（DN）中的作用，并推测β-arrestins可能通过介导足细胞自噬过程参与糖尿病肾损伤。我们首先发现β-arrestin-1和β-arrestin-2在链脲佐菌素诱导的糖尿病小鼠、糖尿病db/db小鼠的肾脏和糖尿病患者的肾脏活检组织中均上调。我们进一步发现，β-arrestin-1或β-arrestin-2缺陷（Arrb 1 −/−或Arrb 2 −/−）可改善糖尿病小鼠的肾损伤。在体外实验中，我们观察到高血糖条件下足细胞β-arrestin-1和β-arrestin-2的表达水平均增加，进一步证明β-arrestin-1和β-arrestin-2通过负调控ATG 12-ATG 5结合抑制足细胞自噬的机制是相同的。总的来说，这项研究首次证明β-arrestin-1和β-arrestin-2介导足细胞自噬活性，表明β-arrestins是连接肾损伤以减少DN中自噬的信号转导途径的关键组分。调节这些通路可能是治疗DN患者的创新治疗策略。
β-Arrestins are multifunctional proteins originally identified as negative adaptors of G protein-coupled receptors (GPCRs). Emerging evidence has also indicated that β-arrestins can activate signaling pathways independent of GPCR activation. This study was to elucidate the role of β-arrestins in diabetic nephropathy (DN) and hypothesized that β-arrestins contribute to diabetic renal injury by mediating podocyte autophagic process. We first found that both β-arrestin-1 and β-arrestin-2 were upregulated in the kidney from streptozotocin-induced diabetic mice, diabetic db/db mice and kidney biopsies from diabetic patients. We further revealed that either β-arrestin-1 or β-arrestin-2 deficiency (Arrb1−/− or Arrb2−/−) ameliorated renal injury in diabetic mice. In vitro, we observed that podocytes increased both β-arrestin-1 and β-arrestin-2 expression levels under hyperglycemia condition and further demonstrated that β-arrestin-1 and β-arrestin-2 shared common mechanisms to suppress podocyte autophagy by negative regulation of ATG12–ATG5 conjugation. Collectively, this study for the first time demonstrates that β-arrestin-1 and β-arrestin-2 mediate podocyte autophagic activity, indicating that β-arrestins are critical components of signal transduction pathways that link renal injury to reduce autophagy in DN. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with DN.