Department of Urology, The First Affiliated Hospital of Bengbu Medical College. Bengbu, China.
Department of Urology, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, China.
Exp Cell Res. 2020 Jul 15;392(2):112007. doi: 10.1016/j.yexcr.2020.112007. Epub 2020 Apr 18.
The kidney injury induced by ischemia-reperfusion (IR) usually comes with irreversible renal fibrosis, a process that develops into chronic kidney disease (CKD), but the underlying cellular mechanism has yet to be determined. To test our hypothesis that exosomes are tightly connected with kidney fibrosis following AKI, we studied the role of exosomes and the transfer of specific miRNA among other genetic components in injured tubular epithelial cells (TECs). We utilized an experimental IR mice model to simulate the fibrotic environment in injured tissue and detect the production of exosomes, and found that exosome deficiency could significantly alleviate the degree of kidney fibrosis following IR administration. MiRNA profiling of exosomes extracted from renal tissue samples with or without ischemia-reperfusion injury (IRI) revealed that miR-150 was markedly increased as a compelling profibrotic molecule, as evidenced by the fact that overexpression of miR-150 facilitated renal fibrosis. Exosomes isolated from hypoxia TECs also induced the increased production of miR-150. In cocultured fibroblasts with TECs-derived exosomes, we confirmed a direct uptake of exosomal miR-150 by fibroblasts. Finally, we verified that in vivo ischemia mice pretreated with exosomes enriched in miR-150 developed more profibrotic manifestations. Thus, our current study indicated that TECs have the ability to employ exosomes to initiate the activation and proliferation of fibroblasts via direct shuttling of miR-150-containing exosomes during reparative responses, and that exosome/miR-150 provides the groundwork for research to develop more personalized therapeutic approaches for controlling tissue fibrosis.
缺血再灌注（IR）引起的肾损伤通常伴有不可逆的肾纤维化，这一过程发展为慢性肾脏病（CKD），但其潜在的细胞机制尚未确定。为了验证我们的假设，即外泌体与急性肾损伤（AKI）后肾纤维化密切相关，我们研究了外泌体以及特定 miRNA 和其他遗传成分在受损肾小管上皮细胞（TEC）中的转移在其中的作用。我们利用实验性 IR 小鼠模型模拟损伤组织中的纤维化环境，并检测外泌体的产生，发现外泌体缺乏可显著减轻 IR 给药后肾纤维化的程度。对未发生缺血再灌注损伤（IRI）和发生 IRI 的肾组织样本中外泌体的 miRNA 进行分析，结果显示 miR-150 作为一种强有力的促纤维化分子明显增加，这表明 miR-150 的过表达促进了肾纤维化。缺氧 TEC 分离的外泌体也诱导了 miR-150 的产生增加。在与 TEC 来源的外泌体共培养的成纤维细胞中，我们证实了成纤维细胞对含外泌体 miR-150 的直接摄取。最后，我们验证了体内用富含 miR-150 的外泌体预处理的缺血小鼠表现出更明显的促纤维化表现。因此，我们的研究表明，TEC 能够通过外泌体直接转运 miR-150 样物质，在修复反应中启动成纤维细胞的激活和增殖，外泌体/miR-150 为研究开发更个性化的治疗方法来控制组织纤维化奠定了基础。
