Faculty Collaboration Database

MicroRNA-21 Is Required for Local and Remote Ischemic Preconditioning in Multiple Organ Protection Against Sepsis. Crit Care Med 2017 Jul;45(7):e703-e710

Date

04/25/2017

Pubmed ID

28437377

DOI

10.1097/CCM.0000000000002363

Scopus ID

2-s2.0-85018800421 (requires institutional sign-in at Scopus site)   70 Citations

Abstract

OBJECTIVE: 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.

DESIGN: Laboratory study.

SETTING: University laboratory.

SUBJECTS: 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).

INTERVENTIONS: 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.

MEASUREMENTS AND MAIN RESULTS: 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.

CONCLUSION: 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.

Author List

Jia P, Wu X, Dai Y, Teng J, Fang Y, Hu J, Zou J, Liang M, Ding X

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Apoptosis Regulatory Proteins
Disease Models, Animal
Hypoxia-Inducible Factor 1, alpha Subunit
Inflammation Mediators
Ischemic Preconditioning
Kidney
Mice
Mice, Inbred C57BL
MicroRNAs
Multiple Organ Failure
NF-kappa B
RNA-Binding Proteins
Sepsis
Up-Regulation