Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
Department of Nephrology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China.
Int J Mol Med. 2022 Sep;50(3). doi: 10.3892/ijmm.2022.5172. Epub 2022 Jul 7.
Tubule injury is a characteristic pathological feature of acute kidney injury (AKI) and determines the prognosis of kidney disease. However, the exact mechanism of tubule injury remains largely unclear. In the present study, the exact mechanism of tubule injury was investigated. Bilateral renal ischemia/reperfusion (I/R) injury (I/RI) was induced in mice and exosome secretion inhibitor GW4869 and miRNA‑155 inhibitor were used. In addition, the exosomal microRNA (miR)‑155‑mediated cross‑talk between macrophage and tubular cells was also investigated. It was determined that tubular injury was observed in an I/R‑induced AKI model, which was closely associated with macrophage infiltration. Interestingly, blocking exosome production using GW4869 ameliorated tubular injury in I/R‑induced AKI. Mechanistically, once released, activated macrophage‑derived exosomal miR‑155 was internalized by tubular cells, resulting in increased tubule injury through targeting of suppressor of cytokine signaling‑1 (SOCS‑1), a negative regulator of NF‑κB signaling. In addition, a dual‑luciferase reporter assay confirmed that SOCS‑1 was the direct target of miR‑155 in tubular cells. Notably, injection of these miR‑155‑enriched exosomes into renal parenchyma resulted in increased tubule injury . Thus, the present study demonstrated that exosomal miR‑155 mediated the communication between activated macrophages and injured tubules, leading to progression of AKI, which not only provide novel insights into the pathophysiology of AKI but also offer a new therapeutic strategy for kidney diseases.
小管损伤是急性肾损伤 (AKI) 的特征性病理特征，决定了肾脏疾病的预后。然而，小管损伤的确切机制在很大程度上仍不清楚。在本研究中，研究了小管损伤的确切机制。在小鼠中诱导双侧肾缺血/再灌注 (I/R) 损伤 (I/RI)，并使用外泌体分泌抑制剂 GW4869 和 miRNA-155 抑制剂。此外，还研究了外泌体 miRNA (miR)-155 介导的巨噬细胞与肾小管细胞之间的串扰。结果确定，在 I/R 诱导的 AKI 模型中观察到小管损伤，这与巨噬细胞浸润密切相关。有趣的是，使用 GW4869 阻断外泌体的产生可改善 I/R 诱导的 AKI 中的小管损伤。从机制上讲，一旦释放，激活的巨噬细胞衍生的外泌体 miR-155 被肾小管细胞内化，通过靶向 NF-κB 信号通路的负调节剂细胞因子信号转导抑制因子 1 (SOCS-1)，导致肾小管损伤增加。此外，双荧光素酶报告基因检测证实 SOCS-1 是肾小管细胞中 miR-155 的直接靶标。值得注意的是，将这些富含 miR-155 的外泌体注射到肾实质中会导致肾小管损伤增加。因此，本研究表明，外泌体 miR-155 介导了激活的巨噬细胞和受损的肾小管之间的通讯，导致 AKI 的进展，这不仅为 AKI 的病理生理学提供了新的见解，而且为肾脏疾病提供了新的治疗策略。
