Inhibiting Rab27a in renal tubular epithelial cells attenuates the inflammation of diabetic kidney disease through the miR-26a-5p/CHAC1/NF-κB pathway
Inhibiting Rab27a in renal tubular epithelial cells attenuates the inflammation of diabetic kidney disease through the miR-26a-5p/CHAC1/NF-κB pathway
复制标题
抑制肾小管上皮细胞中的 Rab27a 通过 miR-26a-5p/CHAC1/NF-kB 通路减轻糖尿病肾病的炎症
DOI：
10.1016/j.lfs.2020.118347
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发表时间：
2020-11-15
期刊：
影响因子：
6.1
通讯作者：
Xue, Yaoming
中科院分区：
文献类型：
--
作者：
Li, Shuangshuang;Jia, Yijie;Xue, Yaoming
外泌体对参与细胞间通讯的受体细胞的影响已被广泛研究，但外泌体对供体细胞的影响仍不清楚。已有研究表明，肾近端小管上皮细胞（PTECs）在不同刺激下分泌的外泌体可加速急性和慢性肾脏疾病的发生。本研究旨在探讨通过敲除关键外泌体调节基因Rab 27 a来抑制PTECs外泌体分泌是否能抑制PTECs过度炎症反应并延缓糖尿病肾病（DKD）。首先，我们证明了在HK-2细胞中牛血清白蛋白（BSA）诱导的炎症反应通过敲除Rab 27 a而被抑制，并且在HFD/STZ诱导的糖尿病小鼠模型中Rab 27 a、IL-6、TNF-α和COL-1表达显著增加。此外，BSA处理的HK-2细胞分泌的外泌体中的miR-26 a-5 p表达显著增加，但在细胞中相应地降低;敲除Rab 27 a后，细胞中的miR-26 a-5 p水平反弹。接下来，我们证实miR-26 a-5 p模拟物抑制了炎症反应，而miR-26 a-5 p抑制剂加速了炎症反应。然后，我们发现miR-26 a-5 p靶向CHAC 1的3 '-非翻译区（UTR）。此外，CHAC 1敲除消除了miR-26 a-5 p抑制剂诱导的炎症反应和NF-κ B信号通路激活。因此，我们得出结论，通过抑制BSA诱导的PTECs的外泌体分泌，促进细胞中miR-26 a-5 p的表达，从而抑制CHAC 1/NF-κ B通路，以防止PTECs中的炎症反应并延迟DKD的发展。本研究为深入了解外泌体的致病机制和DKD的治疗提供了新的靶点。
The effect of exosomes on receptor cells participating in intercellular communication has been extensively studied, but the effect of exosomes on donor cells remains unclear. It has been reported that exosomes secreted by renal proximal tubular epithelial cells (PTECs) under different stimuli accelerate acute and chronic kidney diseases. This study aimed to explore whether inhibiting exosomal secretion in PTECs by knocking out Rab27a, a key exosome regulatory gene, inhibits the excessive inflammatory response in PTECs and delays diabetic kidney disease (DKD). First, we proved that the bovine serum albumin (BSA)-induced inflammatory response in HK-2 cells was inhibited by knocking out Rab27a and that Rab27a, IL-6, TNF-alpha and COL-1 expression was markedly increased in an HFD/STZ-induced diabetic mouse model. Furthermore, miR-26a-5p expression in exosomes secreted by BSA-treated HK-2 cells was significantly increased but correspondingly decreased in the cells; after knocking out Rab27a, miR-26a-5p levels in the cells rebounded. Next, we confirmed that a miR-26a-5p mimic suppressed the inflammatory response, while a miR-26a-5p inhibitor accelerated the inflammatory response. Then, we found that miR-26a-5p targets the 3'-untranslated region (UTR) of CHAC1. Furthermore, the inflammatory response and NF-kappa B signalling pathway activation induction by the miR-26a-5p inhibitor were abolished by CHAC1 knockout. Therefore, we conclude that inhibiting exosome secretion by BSA-induced PTECs promotes miR-26a-5p expression in cells, thereby inhibiting the CHAC1/NF-kappa B pathways to prevent the inflammatory response in PTECs and delaying the development of DKD. This study provides new insight into the pathogenic mechanism of exosomes and a new therapeutic target for DKD.