MicroRNA-21 Is Required for Local and Remote Ischemic Preconditioning in Multiple Organ Protection Against Sepsis

• Published in: Critical care medicine Vol. 45; no. 7; p. e703
• Main Authors: Jia, Ping, Wu, Xiaoli, Dai, Yan, Teng, Jie, Fang, Yi, Hu, Jiachang, Zou, Jianzhou, Liang, Mingyu, Ding, Xiaoqiang
• Format: Journal Article
• Language: English
• Published: United States 01.07.2017
• Subjects: Animals; Apoptosis - physiology; Apoptosis Regulatory Proteins - biosynthesis; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis; Inflammation Mediators - metabolism; Ischemic Preconditioning - methods; Kidney - blood supply; Mice; Mice, Inbred C57BL; MicroRNAs - biosynthesis; Multiple Organ Failure - etiology; Multiple Organ Failure - prevention & control; NF-kappa B - biosynthesis; RNA-Binding Proteins - biosynthesis; Sepsis - complications; Up-Regulation
• ISSN: 1530-0293
• DOI: 10.1097/CCM.0000000000002363

Sepsis, triggered by microbial infection, is a common and life-threatening systemic illness, often leads to impaired function of vital organs. Ischemic preconditioning induced by transient brief episodes of ischemia is a powerful innate mechanism of organ protection. We have reported that a 15-minute renal ischemic preconditioning substantially attenuated subsequent renal ischemia-reperfusion injury. Here, we investigate whether a brief ischemia and reperfusion in kidney can provide protection at local and remote sites against sepsis-induced organ injury, and whether this protection is microRNA-21 dependent. Laboratory study. University laboratory. Mouse renal tubular epithelial cells, C57BL/6 J wildtype (Animal Center of Fudan University, Shanghai, China) and microRNA-21-/- mice (B6.129-Mir21atm1Smoc, Shanghai Biomodel Organism Science & Technology Development Co. Shanghai, China). Mouse renal tubular epithelial cells were treated with hypoxia (2% oxygen). Renal ischemic preconditioning was induced by bilateral renal pedicle clamping for 15 minutes, and sepsis was induced by a single intraperitoneal injection of lipopolysaccharide at a dose of 20 mg/kg or cecal ligation and puncture in mice. Mice treated with renal ischemic preconditioning were protected from endotoxemia or polymicrobial sepsis-induced multiple organ injury, including kidneys, heart, liver, and lungs. Renal ischemic preconditioning induced activation of hypoxia-inducible factor-1α in kidneys, which up-regulated microRNA-21 at transcriptional level, subsequently, leading to increased expression of microRNA-21 in serum exosomes and remote organs, resulting in decreased apoptosis and reduced proinflammatory cytokines production in these organs. In vivo knockdown of microRNA-21 or genetic deletion of microRNA-21 abrogated the organoprotective effects conferred by renal ischemic preconditioning. Mechanistically, we discovered that knockdown of microRNA-21 increased programmed cell death protein 4 expression and nuclear factor-kappa B activity, decreased expression of anti-apoptotic B-cell lymphoma-2. MicroRNA-21 is required for local and remote ischemic preconditioning in multiple organ protection against sepsis, and up-regulation of miR-21 may be a potential therapy for sepsis.