title: Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1.
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-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.
authors.affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Brennan
authors.forename: Karen A
authors.initials: KA
authors.lastname: Nolan
authors.forename: Emma
authors.initials: E
authors.lastname: Börgeson
authors.forename: Oisín S
authors.initials: OS
authors.lastname: Gough
authors.forename: Caitríona M
authors.initials: CM
authors.lastname: McEvoy
authors.forename: Neil G
authors.initials: NG
authors.lastname: Docherty
authors.forename: Debra F
authors.initials: DF
authors.lastname: Higgins
authors.forename: Madeline
authors.initials: M
authors.lastname: Murphy
authors.forename: Denise M
authors.initials: DM
authors.lastname: Sadlier
authors.forename: Syed Tasadaque
authors.initials: ST
authors.lastname: Ali-Shah
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Guiry
authors.forename: David A
authors.initials: DA
authors.lastname: Savage
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
mesh_terms: D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005353:Fibronectins / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D044045:Lipoxins / Q000494:pharmacology*; D035683:MicroRNAs / Q000187:drug effects / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D019699:Thrombospondins / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D015820:Cadherins; D005353:Fibronectins; D044045:Lipoxins; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D019699:Thrombospondins; D053773:Transforming Growth Factor beta1; C040527:lipoxin A4; C487931:mirnlet7 microRNA, human