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MicroRNA-146a in Human and Experimental Ischemic AKI: CXCL8-Dependent Mechanism of Action

Authors
  • Amrouche, Lucile
  • Desbuissons, Geoffroy
  • Rabant, Marion
  • Sauvaget, Virginia
  • Nguyen, Clément
  • Benon, Aurélien
  • Barre, Pauline
  • Rabaté, Clémentine
  • Lebreton, Xavier
  • Gallazzini, Morgan
  • Legendre, Christophe
  • Fabiola Terzi
  • Anglicheau, Dany
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology (ASN)
Publication Date
Jul 28, 2016
Volume
28
Issue
2
Pages
479–493
Identifiers
DOI: 10.1681/asn.2016010045
PMID: 27444565
PMCID: PMC5280013
Source
USPC - SET - SVS
License
Green

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.

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