β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis.
β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis.
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β-连环蛋白控制的肾小管细胞源性外泌体通过 OPN-CD44 轴在成纤维细胞激活中发挥关键作用
DOI：
10.1002/jev2.12203
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发表时间：
2022-03
影响因子：
16
通讯作者：
Zhou L
中科院分区：
文献类型：
--
作者：
Chen S;Zhang M;Li J;Huang J;Zhou S;Hou X;Ye H;Liu X;Xiang S;Shen W;Miao J;Hou FF;Liu Y;Zhou L
肾小管损伤和外周成纤维细胞活化是慢性肾脏病（CKD）的标志，表明两种类型的细胞之间存在密切联系。然而，其根本机制仍有待确定。外泌体在将蛋白质和其他物质穿梭到受体细胞中起作用。在我们的研究中，我们发现外泌体在肾小管细胞中被β-catenin激活。骨桥蛋白（OPN），特别是其N末端片段（N-OPN），被包裹在β-连环蛋白控制的肾小管细胞来源的外泌体货物中，随后传递到成纤维细胞。外泌体OPN通过与CD 44结合促进成纤维细胞增殖和活化。肾小管细胞中β-catenin的基因缺失（Ksp-β-catenin−/−）或CD 44的基因消除（CD 44 −/−）大大改善了肾纤维化。值得注意的是，N-OPN由外泌体携带并分泌到CKD患者的尿液中，与肾功能呈负相关。来自CKD患者的尿外泌体极大地加速了肾纤维化，这被CD 44缺失所阻断。这些结果表明，外泌体介导的OPN/CD 44轴活化在肾纤维化中起关键作用，这是由β-连环蛋白控制的。
Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between the two types of cells. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that exosomes were aroused by β‐catenin in renal tubular cells. Osteopontin (OPN), especially its N‐terminal fragment (N‐OPN), was encapsulated in β‐catenin‐controlled tubular cell‐derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of β‐catenin in tubular cells (Ksp‐β‐catenin−/−) or gene ablation of CD44 (CD44−/−) greatly ameliorated renal fibrosis. Notably, N‐OPN was carried by exosome and secreted into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome‐mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by β‐catenin.
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