Injured tubular epithelial cells activate fibroblasts to promote kidney fibrosis through miR-150-containing exosomes
Injured tubular epithelial cells activate fibroblasts to promote kidney fibrosis through miR-150-containing exosomes
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DOI：
10.1016/j.yexcr.2020.112007
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发表时间：
2020-07-15
影响因子：
3.7
通讯作者：
Chen, Ming
中科院分区：
文献类型：
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作者：
Guan, Han;Peng, Rui;Chen, Ming
缺血再灌注(IR)引起的肾脏损伤通常伴随不可逆的肾纤维化，发展为慢性肾脏疾病(CKD)，但其潜在的细胞机制尚不清楚。为了验证我们的假设，即Exosome与AKI后的肾脏纤维化密切相关，我们研究了Exosome在受损的肾小管上皮细胞(TECs)中的作用以及特定miRNA在其他遗传成分中的转移。我们利用实验性IR小鼠模型来模拟损伤组织的纤维化环境，并检测Exosome的产生，发现Exosome缺乏可以显著减轻IR后肾脏纤维化的程度。从有或无缺血再灌注损伤(IRI)的肾组织中提取的外切体的miRNA图谱显示，miR-150作为一种引人注目的促纤维化分子显著增加，这一事实证明miR-150的过表达促进了肾脏纤维化。从缺氧的TECs中分离的外切体也能诱导miR-150的产生增加。在与TECs来源的外切体共培养的成纤维细胞中，我们证实成纤维细胞直接摄取了外切体miR-150。最后，我们验证了用富含miR-150的外切体预处理的体内缺血小鼠出现了更多的纤维化表现。因此，我们目前的研究表明，TECs有能力利用Exosome在修复反应期间通过直接穿梭含有miR-150的Exosome来启动成纤维细胞的激活和增殖，并且Exosome/miR-150为研究开发更个性化的治疗方法来控制组织纤维化提供了基础。
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.