Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1

Eoin P Brennan, Karen A Nolan, Emma Börgeson, Oisín S Gough, Caitríona M McEvoy, Neil G Docherty, Debra F Higgins, Madeline Murphy, Denise M Sadlier, Syed Tasadaque Ali-Shah, Patrick J Guiry, David A Savage, Alexander P Maxwell, Finian Martin, Catherine Godson, GENIE Consortium, Amy McKnight, Gareth McKay

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)

Abstract

Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA4) attenuated TGF-ß1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-ß1 suppressed expression of let-7c. In cells pretreated with LXA4, upregulation of let-7c persisted despite subsequent stimulation with TGF-ß1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA4 analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-ß1 signaling pathway, including the TGF-ß receptor type 1. Consistent with this, LXA4-induced upregulation of let-7c inhibited both the expression of TGF-ß receptor type 1 and the response to TGF-ß1. Overexpression of let-7c mimicked the antifibrotic effects of LXA4 in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA4. Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA4-mediated upregulation of let-7c suppresses TGF-ß1-induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis.
Original languageEnglish
Pages (from-to)627-637
JournalJournal of the American Society of Nephrology
Volume24
Issue number4
Early online date21 Mar 2013
DOIs
Publication statusPublished - Apr 2013

Keywords

  • Lipoxins
  • MicroRNAs
  • Fibrosis
  • Humans
  • Cadherins
  • Transforming Growth Factor beta1
  • Receptor, Notch1
  • Cells, Cultured
  • Thrombospondins
  • Fibronectins
  • Kidney
  • Kidney Tubules, Proximal
  • Signal Transduction

ASJC Scopus subject areas

  • Nephrology

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