Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys.
Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys.
复制标题
来自肾小管细胞的外泌体 miR-21 通过靶向阻塞肾脏中的 PTEN 激活成纤维细胞，从而促进肾纤维化
作者：
Zhao S;Li W;Yu W;Rao T;Li H;Ruan Y;Yuan R;Li C;Ning J;Li S;Chen W;Cheng F;Zhou X
原理：输尿管梗阻引起的肾积水与肾纤维化和进行性慢性肾脏病（CKD）相关。外泌体介导的细胞间通讯已被认为参与各种疾病，包括肾纤维化。然而，关于外泌体如何调节阻塞肾脏中的肾纤维化知之甚少。研究方法：我们首先检查了UUO（单侧输尿管梗阻）小鼠肾脏和TGF-β1刺激的肾小管上皮细胞（NRK-52 E）中外泌体的分泌。随后收获来自NRK-52 E细胞的外来体，并与成纤维细胞（NRK-49 F）一起孵育或通过尾静脉注射到UUO小鼠中。我们接下来构建Rab 27 a敲除小鼠以进一步证实外泌体介导的上皮-成纤维细胞通讯在UUO小鼠中与肾纤维化相关的作用。采用高通量miRNA测序技术检测TGFβ1-Exos的miRNA谱。通过设定特定的miRNA模拟物、miRNA抑制剂、siRNA或miRNA LNA组，预测和评价候选miRNA及其靶基因和相关通路在体外和体内的作用。结果如下：肾纤维化增加与UUO天数延长相关，UUO肾和TGF-β1刺激的NRK-52 E细胞外泌体分泌显著增加。纯化的TGF-β1刺激的NRK-52 E细胞exosomes可激活成纤维细胞，加重肾纤维化。此外，通过Rab 27 a敲除或GW 4869处理抑制外泌体分泌消除了成纤维细胞活化并改善了肾纤维化。与对照组相比，TGFβ1-Exos组的外泌体miR-21表达显著增加，PTEN是miR-21的特定靶点。促进或抑制上皮外泌体miR-21相应地加速或消除体外成纤维细胞活化，并且miR-21缺陷的外泌体通过PTEN/Akt途径在体内减轻UUO后的肾纤维化。结论：我们的研究结果表明，来自肾小管上皮细胞的外泌体miR-21可能通过miR-21/PTEN/Akt途径激活阻塞肾脏中的成纤维细胞来加速肾纤维化的发展。
Rationale: Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and progressive chronic kidney disease (CKD). Exosome-mediated cell-cell communication has been suggested to be involved in various diseases, including renal fibrosis. However, little is known regarding how exosomes regulate renal fibrosis in obstructed kidneys. Methods: We first examined the secretion of exosomes in UUO (unilateral ureteral obstruction) mouse kidneys and TGF-β1-stimulated tubular epithelial cells (NRK-52E). Exosomes from NRK-52E cells were subsequently harvested and incubated with fibroblasts (NRK-49F) or injected into UUO mice via the tail vein. We next constructed Rab27a knockout mice to further confirm the role of exosome-mediated epithelial-fibroblast communication relevant to renal fibrosis in UUO mice. High-throughput miRNA sequencing was performed to detect the miRNA profiles of TGFβ1-Exos. The roles of candidate miRNAs, their target genes and relevant pathways were predicted and assessed in vitro and in vivo by setting specific miRNA mimic, miRNA inhibitor, siRNA or miRNA LNA groups. Results: Increased renal fibrosis was associated with prolonged UUO days, and the secretion of exosomes was markedly increased in UUO kidneys and TGF-β1-stimulated NRK-52E cells. Purified exosomes from TGF-β1-stimulated NRK-52E cells could activate fibroblasts and aggravate renal fibrosis in vitro and in vivo. In addition, the inhibition of exosome secretion by Rab27a knockout or GW4869 treatment abolished fibroblast activation and ameliorated renal fibrosis. Exosomal miR-21 was significantly increased in TGFβ1-Exos compared with Ctrl-Exos, and PTEN is a certain target of miR-21. The promotion or inhibition of epithelial exosomal miR-21 correspondingly accelerated or abolished fibroblast activation in vitro, and renal fibrosis after UUO was alleviated by miR-21-deficient exosomes in vivo through the PTEN/Akt pathway. Conclusion: Our findings reveal that exosomal miR-21 from tubular epithelial cells may accelerate the development of renal fibrosis by activating fibroblasts via the miR-21/PTEN/Akt pathway in obstructed kidneys.
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影响因子：
3.7
作者：
Dominguez JM 2nd;Dominguez JH;Xie D;Kelly KJ
通讯作者：
Kelly KJ
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
13.6
作者：
Borges, Fernanda T.;Melo, Sonia A.;Kalluri, Raghu
通讯作者：
Kalluri, Raghu
影响因子：
4
作者：
Luo, Qihan;Cai, Zhaowei;Cai, Yueqin
通讯作者：
Cai, Yueqin
影响因子：
4.3
作者：
Jadli, Anshul S.;Ballasy, Noura;Patel, Vaibhav B.
通讯作者：
Patel, Vaibhav B.