Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10, Youanmenwai, Xitoutiao, Fengtai District, Beijing, 100069, China.
Beijing Children's Hospital, Capital Medical University, NO. 56, Nanlishi Road, Xi Cheng District, Beijing, 100045, China.
Sci Rep. 2017 Aug 24;7(1):9371. doi: 10.1038/s41598-017-09907-6.
New data indicate that abnormal glomerular endothelial cell (GEC)-podocyte crosstalk plays a critical role in diabetic nephropathy (DN). The aim of our study is to investigate the role of exosomes from high glucose (HG)-treated GECs in the epithelial-mesenchymal transition (EMT) and dysfunction of podocytes. In this study, exosomes were extracted from GEC culture supernatants and podocytes were incubated with the GEC-derived exosomes. Here, we demonstrate that HG induces the endothelial-mesenchymal transition (EndoMT) of GECs and HG-treated cells undergoing the EndoMT secrete more exosomes than normal glucose (NG)-treated GECs. We show that GEC-derived exosomes can be internalized by podocytes and exosomes from HG-treated cells undergoing an EndoMT-like process can trigger the podocyte EMT and barrier dysfunction. Our study reveals that TGF-β1 mRNA is enriched in exosomes from HG-treated GECs and probably mediates the EMT and dysfunction of podocytes. In addition, our experimental results illustrate that canonical Wnt/β-catenin signaling is involved in the exosome-induced podocyte EMT. Our findings suggest the importance of paracrine communication via exosomes between cells undergoing the EndoMT and podocytes for renal fibrosis in DN. Thus, protecting GECs from the EndoMT and inhibiting TGF-β1-containing exosomes release from GECs is necessary to manage renal fibrosis in DN.
新数据表明，异常的肾小球内皮细胞（GEC）-足细胞串扰在糖尿病肾病（DN）中起着关键作用。我们的研究目的是探讨高糖（HG）处理的 GEC 来源的外泌体在足细胞上皮-间充质转化（EMT）和功能障碍中的作用。在这项研究中，从 GEC 培养上清液中提取外泌体，并将足细胞与 GEC 来源的外泌体孵育。在这里，我们证明 HG 诱导 GEC 的内皮-间充质转化（EndoMT），并且经历 EndoMT 的 HG 处理的细胞比正常葡萄糖（NG）处理的 GEC 分泌更多的外泌体。我们表明 GEC 来源的外泌体可以被足细胞内化，并且经历 EndoMT 样过程的 HG 处理的细胞来源的外泌体可以触发足细胞 EMT 和屏障功能障碍。我们的研究表明，TGF-β1 mRNA 在 HG 处理的 GEC 来源的外泌体中富集，并且可能介导足细胞的 EMT 和功能障碍。此外，我们的实验结果表明，经典的 Wnt/β-catenin 信号通路参与了外泌体诱导的足细胞 EMT。我们的发现表明，经历 EndoMT 的细胞与足细胞之间通过外泌体的旁分泌通讯对 DN 中的肾脏纤维化很重要。因此，保护 GEC 免受 EndoMT 影响并抑制 TGF-β1 含量的外泌体从 GEC 释放对于管理 DN 中的肾脏纤维化是必要的。
