title: MicroRNA-146a in Human and Experimental Ischemic AKI: CXCL8-Dependent Mechanism of Action.
abstract: AKI leads to tubular injury and interstitial inflammation that must be controlled to avoid the development of fibrosis. We hypothesized that microRNAs are involved in the regulation of the balance between lesion formation and adaptive repair. We found that, under proinflammatory conditions, microRNA-146a (miR-146a) is transcriptionally upregulated by ligands of IL-1 receptor/Toll-like receptor family members via the activation of NF-κB in cultured renal proximal tubular cells. In vivo, more severe renal ischemia-reperfusion injury (IRI) associated with increased expression of miR-146a in both allografts and urine of human kidney transplant recipients, and unilateral IRI in mice induced miR-146a expression in injured kidneys. After unilateral IRI, miR-146a-/-mice exhibited more extensive tubular injury, inflammatory infiltrates, and fibrosis than wild-type mice. In vitro, overexpression or downregulation of miR-146a diminished or enhanced, respectively, IL-1 receptor-associated kinase 1 expression and induced similar effects on C-X-C motif ligand 8 (CXCL8)/CXCL1 expression by injured tubular cells. Moreover, inhibition of CXCL8/CXCL1 signaling prevented the development of inflammation and fibrosis after IRI in miR-146a-/-mice. In conclusion, these results indicate that miR-146a is a key mediator of the renal tubular response to IRI that limits the consequences of inflammation, a key process in the development of AKI and CKD.
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.|Paris Descartes, Sorbonne Paris Cité University, Paris, France.|Department of Nephrology and Kidney Transplantation.
authors.forename: Lucile
authors.initials: L
authors.lastname: Amrouche
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Desbuissons
authors.affiliation: Paris Descartes, Sorbonne Paris Cité University, Paris, France.|Department of Pathology, and.
authors.forename: Marion
authors.initials: M
authors.lastname: Rabant
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
authors.forename: Virginia
authors.initials: V
authors.lastname: Sauvaget
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Benon
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Barre
authors.affiliation: Paris Descartes, Sorbonne Paris Cité University, Paris, France.|Department of Nephrology and Kidney Transplantation.
authors.forename: Clémentine
authors.initials: C
authors.lastname: Rabaté
authors.affiliation: Department of Nephrology and Kidney Transplantation.
authors.forename: Xavier
authors.initials: X
authors.lastname: Lebreton
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
authors.forename: Morgan
authors.initials: M
authors.lastname: Gallazzini
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.|Paris Descartes, Sorbonne Paris Cité University, Paris, France.|Department of Nephrology and Kidney Transplantation.|Réseau Thématique de Recherche et de Soins Centaure, Labex Transplantex, Necker Hospital, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Terzi
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France; dany.anglicheau@nck.aphp.fr.|Paris Descartes, Sorbonne Paris Cité University, Paris, France.|Department of Nephrology and Kidney Transplantation.|Réseau Thématique de Recherche et de Soins Centaure, Labex Transplantex, Necker Hospital, Paris, France.
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000235:genetics*; D000818:Animals; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D015427:Reperfusion Injury
chemical_list: D016209:Interleukin-8; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse
keywords: Cell Signaling; delayed graft function; fibrosis; ischemia-reperfusion; mRNA; renal epithelial cell