Exosomal miRNA-19b-3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury
Exosomal miRNA-19b-3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury
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DOI：
10.1038/s41418-019-0349-y
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发表时间：
2020-01-01
影响因子：
12.4
通讯作者：
Liu, Bi-Cheng
中科院分区：
文献类型：
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作者：
Lv, Lin-Li;Feng, Ye;Liu, Bi-Cheng
肾小管间质炎症是急、慢性肾损伤的共同特征。然而，肾小管上皮细胞（TEC）的初始损伤驱动间质炎症的机制仍不清楚。本文旨在探讨来源于TEC的外泌体miRNA在肾小管间质炎症发生中的作用。在LPS诱导的急性肾损伤（阿基）小鼠模型中检查了肾外来体的总体微小RNA（miRNA）表达谱，并且miR-19 b-3 p被鉴定为与对照相比在TEC衍生的外来体中最显著增加的miRNA。在阿霉素（ADR）诱导的慢性蛋白尿肾病模型中也发现了类似的结果，其中外泌体miR-19 b-3 p显著释放。有趣的是，一旦释放，TEC衍生的外泌体miR-19 B-3 p被巨噬细胞内化，通过靶向NF-κ B/SOCS-1导致M1表型极化。双荧光素酶报告基因检测证实SOCS-1是miR-19 b-3 p的直接靶点。重要的是，外泌体miR-19 b-3 p在引发肾脏炎症中的致病作用通过过继转移纯化的TEC衍生的外泌体以在小鼠中引起肾小管间质炎症的能力来揭示，这通过抑制miR-19 b-3 p来逆转。临床上，在尿外泌体中发现高水平的miR-19 b-3 p，并且与糖尿病肾病患者肾小管间质炎症的严重程度相关。因此，我们的研究表明，外泌体miR-19 b-3 p介导了受损TEC和巨噬细胞之间的通讯，导致M1巨噬细胞活化。外泌体/miR 19 b-3 p/SOCS 1轴在肾小管间质炎症中发挥关键的病理作用，代表肾脏疾病的新治疗靶点。
Tubulointerstitial inflammation is a common characteristic of acute and chronic kidney injury. However, the mechanism by which the initial injury of tubular epithelial cells (TECs) drives interstitial inflammation remains unclear. This paper aims to explore the role of exosomal miRNAs derived from TECs in the development of tubulointerstitial inflammation. Global microRNA(miRNA) expression profiling of renal exosomes was examined in a LPS induced acute kidney injury (AKI) mouse model and miR-19b-3p was identified as the miRNA that was most notably increased in TEC-derived exosomes compared to controls. Similar results were also found in an adriamycin (ADR) induced chronic proteinuric kidney disease model in which exosomal miR-19b-3p was markedly released. Interestingly, once released, TEC-derived exosomal miR-19b-3p was internalized by macrophages, leading to M1 phenotype polarization through targeting NF-kappa B/SOCS-1. A dual-luciferase reporter assay confirmed that SOCS-1 was the direct target of miR-19b-3p. Importantly, the pathogenic role of exosomal miR-19b-3p in initiating renal inflammation was revealed by the ability of adoptively transferred of purified TEC-derived exosomes to cause tubulointerstitial inflammation in mice, which was reversed by inhibition of miR-19b-3p. Clinically, high levels of miR-19b-3p were found in urinary exosomes and were correlated with the severity of tubulointerstitial inflammation in patients with diabetic nephropathy. Thus, our studies demonstrated that exosomal miR-19b-3p mediated the communication between injured TECs and macrophages, leading to M1 macrophage activation. The exosome/miR19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation, representing a new therapeutic target for kidney disease.