Delayed Remote Ischemic Preconditioning Confers Renoprotection against Septic Acute Kidney Injury via Exosomal miR-21
Delayed Remote Ischemic Preconditioning Confers Renoprotection against Septic Acute Kidney Injury via Exosomal miR-21
复制标题
延迟远程缺血预处理通过外泌体 miR-21 提供针对脓毒性急性肾损伤的肾脏保护作用
DOI：
10.7150/thno.29832
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Din, Xiaoqiang
中科院分区：
文献类型：
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作者：
Pan, Tianyi;Chen, Nan;Din, Xiaoqiang
脓毒症是一种常见的危及生命的全身性疾病，常导致多器官的急性损伤。本研究表明，由股动脉短暂缺血和再灌注引起的远端缺血预处理（rIPC）对脓毒症诱导的急性肾损伤（AKI）具有保护作用。方法：在盲肠结扎穿刺（CLP）开始前24 h，在小鼠体内进行肢体rIPC，并将rIPC小鼠的血清外泌体输注到CLP激发的受体中。在体外，我们从经过缺氧和再氧化（H/R）预处理的分化的C2C12细胞（肌管）中提取并鉴定了外泌体，并将外泌体给予脂多糖（LPS）处理的小鼠小管上皮细胞（mTECs）或静脉注射到clp挑战的miR-21敲除小鼠中进行拯救实验。结果：肢体rIPC通过缺氧诱导因子1 α (HIF-1 α)依赖的方式上调miR-21，保护多微生物脓毒症小鼠的多器官功能障碍、炎症细胞因子的系统性积累和加速肺组织细胞凋亡。然而，在miR-21敲除小鼠或后肢肌肉注射HIF-1 α siRNA的小鼠中，肢体rIPC赋予的器官保护被取消。在机制上，我们发现miR-21通过血清外泌体从缺血前肢体转运到远端器官。在肾脏中，经H/R培养的肌管或经rIPC处理的小鼠血清中增强的外泌体miR-21整合到肾小管上皮细胞中，然后靶向下游的PDCD4/NF-kappa B和PTEN/AKT通路，发挥抗炎和抗凋亡作用，从而在体内和体外减轻败血症诱导的肾损伤。结论：本研究证明了外泌体miR-21在肢体rIPC对脓毒症的肾保护中发挥关键作用，并提示rIPC和外泌体可能作为脓毒症所致肾损伤的可能治疗策略。
Sepsis is a common and life-threatening systemic disorder, often leading to acute injury of multiple organs. Here, we show that remote ischemic preconditioning (rIPC), elicited by brief episodes of ischemia and reperfusion in femoral arteries, provides protective effects against sepsis-induced acute kidney injury (AKI).Methods: Limb rIPC was conducted on mice in vivo 24 h before the onset of cecal ligation and puncture (CLP), and serum exosomes derived from rIPC mice were infused into CLP-challenged recipients. In vitro, we extracted and identified exosomes from differentiated C2C12 cells (myotubes) subjected to hypoxia and reoxygenation (H/R) preconditioning, and the exosomes were administered to lipopolysaccharide (LPS)-treated mouse tubular epithelial cells (mTECs) or intravenously injected into CLP-challenged miR-21 knockout mice for rescue experiments.Results: Limb rIPC protected polymicrobial septic mice from multiple organ dysfunction, systemic accumulation of inflammatory cytokines and accelerated parenchymal cell apoptosis through upregulation of miR-21 in a hypoxia-inducible factor 1 alpha (HIF-1 alpha)-dependent manner in the ischemic limbs of mice. However, in miR-21 knockout mice or mice that received HIF-1 alpha siRNA injection into hind limb muscles, the organ protection conferred by limb rIPC was abolished. Mechanistically, we discovered that miR-21 was transported from preischemic limbs to remote organs via serum exosomes. In kidneys, the enhanced exosomal miR-21 derived from cultured myotubes with H/R or the serum of mice treated with rIPC integrated into renal tubular epithelial cells and then targeted the downstream PDCD4/NF-kappa B and PTEN/AKT pathways, exerting anti-inflammatory and anti-apoptotic effects and consequently attenuating sepsis-induced renal injury both in vivo and in vitro.Conclusion: This study demonstrates a critical role for exosomal miR-21 in renoprotection conferred by limb rIPC against sepsis and suggests that rIPC and exosomes might serve as the possible therapeutic strategies for sepsis-induced kidney injury.