Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu Province, 210009, China.
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Liu Che Woo Institute of Innovative Medicine, Chinese University of Hong Kong, Hong Kong, SAR, 999077, China.
Cell Death Differ. 2020 Jan;27(1):210-226. doi: 10.1038/s41418-019-0349-y. Epub 2019 May 16.
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-κB/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/miR-19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation, representing a new therapeutic target for kidney disease.
肾小管间质炎症是急性和慢性肾损伤的共同特征。然而，肾小管上皮细胞 (TEC) 初始损伤驱动间质炎症的机制尚不清楚。本文旨在探讨源自 TEC 的外泌体 miRNAs 在肾小管间质炎症发展中的作用。在 LPS 诱导的急性肾损伤 (AKI) 小鼠模型中检查了肾外泌体的全局 microRNA (miRNA) 表达谱，发现与对照组相比，TEC 来源的外泌体中 miRNA-19b-3p 显著增加。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-19b-3p 明显释放。有趣的是，一旦释放，TEC 来源的外泌体 miR-19b-3p 被巨噬细胞内化，通过靶向 NF-κB/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-19b-3p 的直接靶标。重要的是，通过纯化的 TEC 衍生外泌体的过继转移能力，揭示了外泌体 miR-19b-3p 在引发肾脏炎症中的致病作用，抑制 miR-19b-3p 可逆转这一作用。临床上，在尿外泌体中发现 miR-19b-3p 水平升高，并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-19b-3p 介导了受损 TEC 与巨噬细胞之间的通讯，导致 M1 巨噬细胞活化。外泌体/miR-19b-3p/SOCS1 轴在肾小管间质炎症中发挥着关键的病理作用，代表了肾脏疾病的一个新的治疗靶点。
