Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Clin Sci (Lond). 2020 Aug 28;134(16):2223-2234. doi: 10.1042/CS20200288.
Exosomes have been shown to effectively regulate the biological functions of target cells. Here, we investigated the protective effect and mechanism of hypoxia-induced renal tubular epithelial cells (TECs)-derived exosomes on acute tubular injury. We found that in vitro hypoxia-induced tubular exosomes (Hy-EXOs) were protective in acute tubular injury by promoting TECs proliferation and improving mitochondrial functions. By using exosome miRNA sequencing, we identified miR-20a-5p was abundant and was a key mechanism for the protective effect of Hy-EXOs on tubular injury as up-regulation of miR-20a-5p enhanced but down-regulation of miR-20a-5p inhibited the protective effect of Hy-EXOs on tubular injury under hypoxia conditions. Further study in a mouse model of ischemia-reperfusion-induced acute kidney injury (IRI-AKI) also confirmed this notion as pre-treating mice with the miR-20a-5p agomir 48 h prior to AKI induction was capable of inhibiting IRI-AKI by lowering serum levels of creatinine and urea nitrogen, and attenuating the severity of tubular necrosis, F4/80(+) macrophages infiltration and vascular rarefaction. Mechanistically, the protective effect of miR-20a-5p on acute kidney injury (AKI) was associated with inhibition of TECs mitochondrial injury and apoptosis in vitro and in vivo. In conclusion, miR-20a-5p is enriched in hypoxia-derived tubular exosomes and protects against acute tubular injury. Results from the present study also reveal that miR-20a-5p may represent as a novel therapy for AKI.
外泌体已被证明能有效地调节靶细胞的生物学功能。在这里，我们研究了缺氧诱导的肾小管上皮细胞（TEC）衍生的外泌体对急性肾小管损伤的保护作用及其机制。我们发现，体外缺氧诱导的管状外泌体（Hy-EXOs）通过促进 TEC 增殖和改善线粒体功能，对急性肾小管损伤具有保护作用。通过外泌体 miRNA 测序，我们发现 miR-20a-5p 丰富，是 Hy-EXOs 对管状损伤保护作用的关键机制，上调 miR-20a-5p 增强但下调 miR-20a-5p 抑制缺氧条件下 Hy-EXOs 对管状损伤的保护作用。在缺血再灌注诱导的急性肾损伤（IRI-AKI）小鼠模型中的进一步研究也证实了这一观点，因为在 AKI 诱导前 48 小时用 miR-20a-5p 激动剂预处理小鼠能够通过降低血清肌酐和尿素氮水平，减轻肾小管坏死、F4/80(+)巨噬细胞浸润和血管稀疏的严重程度，从而抑制 IRI-AKI。从机制上讲，miR-20a-5p 对急性肾损伤（AKI）的保护作用与体外和体内 TEC 线粒体损伤和凋亡的抑制有关。总之，miR-20a-5p 在缺氧衍生的管状外泌体中丰富，并能抵抗急性肾小管损伤。本研究结果还表明，miR-20a-5p 可能成为 AKI 的一种新疗法。
