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

J Am Soc Nephrol. 2013 Mar;24(4):627-37. doi: 10.1681/ASN.2012060550. Epub 2013 Mar 21.


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-β1-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-β1 suppressed expression of let-7c. In cells pretreated with LXA4, upregulation of let-7c persisted despite subsequent stimulation with TGF-β1. 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-β1 signaling pathway, including the TGF-β receptor type 1. Consistent with this, LXA4-induced upregulation of let-7c inhibited both the expression of TGF-β receptor type 1 and the response to TGF-β1. 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-β1-induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / drug effects
  • Cadherins / metabolism
  • Cells, Cultured
  • Fibronectins / drug effects
  • Fibronectins / metabolism
  • Fibrosis
  • Humans
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology*
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Lipoxins / pharmacology*
  • MicroRNAs / drug effects
  • MicroRNAs / metabolism*
  • Receptor, Notch1 / drug effects
  • Receptor, Notch1 / metabolism
  • Signal Transduction
  • Thrombospondins / drug effects
  • Thrombospondins / metabolism
  • Transforming Growth Factor beta1 / drug effects
  • Transforming Growth Factor beta1 / metabolism*


  • Cadherins
  • Fibronectins
  • Lipoxins
  • MicroRNAs
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Thrombospondins
  • Transforming Growth Factor beta1
  • lipoxin A4
  • mirnlet7 microRNA, human