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

J Am Soc Nephrol. 2017 Feb;28(2):479-493. doi: 10.1681/ASN.2016010045. Epub 2016 Jul 21.

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.

Keywords: Cell Signaling; delayed graft function; fibrosis; ischemia-reperfusion; mRNA; renal epithelial cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / genetics*
  • Animals
  • Humans
  • Interleukin-8 / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / physiology*
  • Reperfusion Injury

Substances

  • Interleukin-8
  • MIRN146 microRNA, human
  • MicroRNAs
  • Mirn146 microRNA, mouse