Decoy receptor 2 mediation of the senescent phenotype of tubular cells by interacting with peroxiredoxin 1 presents a novel mechanism of renal fibrosis in diabetic nephropathy
Decoy receptor 2 mediation of the senescent phenotype of tubular cells by interacting with peroxiredoxin 1 presents a novel mechanism of renal fibrosis in diabetic nephropathy
复制标题
诱饵受体 2 通过与过氧化还原蛋白 1 相互作用介导肾小管细胞的衰老表型，提出了糖尿病肾病肾纤维化的新机制
DOI：
10.1016/j.kint.2020.03.026
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发表时间：
2020-09-01
影响因子：
19.6
通讯作者：
He Ya-Ni
中科院分区：
文献类型：
--
作者：
Chen Jia;Chen Ke-Hong;He Ya-Ni
肾小管上皮细胞（renaltubular epithelial cell，RTEC）的早衰是糖尿病肾病发生发展的重要环节，与肾脏纤维化密切相关。然而，其潜在机制仍不清楚。本研究旨在探讨诱骗受体2（decoy receptor 2，DcR 2）在肾纤维化和RTEC衰老表型中的作用及其机制。DcR 2在衰老的RTEC中特异性表达，并与糖尿病肾病患者和链脲佐菌素诱导的糖尿病肾病小鼠的肾纤维化相关。在链脲佐菌素诱导的小鼠中，DcR 2的敲低降低了α-平滑肌肌动蛋白、胶原I、纤连蛋白的表达和血清肌酐水平。DcR 2敲低还抑制衰老标记物p16、p21、衰老相关β-半乳糖苷酶和衰老相关异染色质灶的表达，并促进衰老相关分泌表型包括IL-6、TGF-β 1和基质金属蛋白酶2的分泌。然而，DcR 2过表达表现出相反的效果。定量蛋白质组学和验证研究表明，DcR 2与过氧化物氧还蛋白1（PRDX 1）相互作用，调节细胞周期和衰老。在体外，PRDX 1的敲低上调p16和细胞周期蛋白D1，同时下调细胞周期蛋白依赖性激酶6的表达，导致RTEC衰老。此外，PRDX 1敲低促进DcR 2诱导的p16、细胞周期蛋白D1、IL-6和TGF-β 1表达，而PRDX 1过表达导致相反的结果。随后，DcR 2调节PRDX 1磷酸化，这可以被特异性酪氨酸激酶抑制剂genistein抑制。因此，DcR 2通过与PRDX 1相互作用介导RTEC和肾纤维化的衰老表型。因此，DcR 2可能作为改善糖尿病肾病进展的潜在治疗靶点。
Premature senescence of renal tubular epithelial cell (RTEC), which is involved in kidney fibrosis, is a key event in the progression of diabetic nephropathy. However, the underlying mechanism remains unclear. Here we investigated the role and mechanism of decoy receptor 2(DcR2) in kidney fibrosis and the senescent phenotype of RTEC. DcR2 was specifically expressed in senescent RTEC and associated with kidney fibrosis in patients with diabetic nephropathy and mice with streptozotocin-induced with diabetic nephropathy. Knockdown of DcR2 decreased the expression of alpha-smooth muscle actin, collagen I, fibronectin and serum creatinine levels in streptozotocin-induced mice. DcR2 knockdown also inhibited the expression of senescent markers p16, p21, senescence-associated beta-galactosidase and senescence-associated heterochromatic foci and promoted the secretion of a senescence-associated secretory phenotype including IL-6, TGF-beta 1, and matrix metalloproteinase 2 in vitro and in vivo. However, DcR2 overexpression showed the opposite effects. Quantitative proteomics and validation studies revealed that DcR2 interacted with peroxiredoxin 1 (PRDX1), which regulated the cell cycle and senescence. Knockdown of PRDX1 upregulated p16 and cyclin D1 while downregulating cyclin-dependent kinase 6 expression in vitro, resulting in RTEC senescence. Furthermore, PRDX1 knockdown promoted DcR2-induced p16, cyclin D1, IL-6, and TGF-beta 1 expression, whereas PRDX1 overexpression led to the opposite results. Subsequently, DcR2 regulated PRDX1 phosphorylation, which could be inhibited by the specific tyrosine kinase inhibitor genistein. Thus, DcR2 mediated the senescent phenotype of RTEC and kidney fibrosis by interacting with PRDX1. Hence, DcR2 may act as a potential therapeutic target for the amelioration of diabetic nephropathy progression.