title: miR-146a is essential for lipopolysaccharide (LPS)-induced cross-tolerance against kidney ischemia/reperfusion injury in mice.
abstract: MicroRNA-146a is one of most important microRNAs involved in development of endotoxin tolerance via (toll-like receptors) TLRs/ NF-κB pathway. In this study, we sought to identify the mechanistic role of miR-146a in mediating the protective effect of lipopolysaccharide (LPS) pretreatment on kidney ischemia/reperfusion injury. A locked nucleic acid-modified anti-miR-146a given before LPS treatment knocked down miR-146a expression and completely negated LPS-mediated protection against kidney ischemia/reperfusion injury. Knockdown of miR-146a resulted in significantly higher histopathological scores for tubular damage, expression of proinflammatory cytokines and chemokines, and neutrophil and macrophage infiltration. Furthermore, knockdown of miR-146a greatly up-regulated the protein levels of IL-1 receptor-associated kinase (IRAK-1) and tumor-necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which are known target genes of miR-146a, leading to activation of NF-κB. Finally, elevation of nuclear translocation of NF-κB p65/p50 and caspase-3 expression, degradation of cytosolic IkBα and BcL-xL, and substantially exacerbation of tubular cell apoptosis were inversely correlated with miR-146a expression. Taken together, our results identify that miR146a exerts a kidney protective effect through negative regulation of acute inflammatory response by suppressing NF-κB activation and proinflammatory genes expression.
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.|Kidney and Dialysis Institute of Shanghai, Shanghai, China.|Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.|Kidney and Dialysis Institute of Shanghai, Shanghai, China.|Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Jia
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.|Kidney and Dialysis Institute of Shanghai, Shanghai, China.|Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Kidney Section, James J Peter Veteran Administration Medical Center at Bronx, NY, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: He
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.|Kidney and Dialysis Institute of Shanghai, Shanghai, China.|Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Ding
mesh_terms: D021581:Active Transport, Cell Nucleus; D058186:Acute Kidney Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D065840:Protective Factors; D034622:RNA Interference; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D009841:Oligonucleotides; D048029:TNF Receptor-Associated Factor 6; C477371:locked nucleic acid; D053592:Interleukin-1 Receptor-Associated Kinases