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Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1
Eoin P Brennan1, Karen A Nolan, Emma Börgeson
1Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
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.
Insights
Lipoxin A4 (LXA4) reduces kidney fibrosis by upregulating microRNA let-7c, which inhibits TGF-β1 signaling. This finding offers a new therapeutic target for treating renal fibrosis.
Area of Science:
- Renal pathophysiology
- Molecular biology
- Inflammation resolution
Background:
- Lipoxins are endogenous lipid mediators that resolve inflammation.
- Lipoxins may inhibit fibrosis, suggesting a role in renal disease.
- Transforming growth factor-beta 1 (TGF-β1) is implicated in renal fibrosis.
Purpose of the Study:
- To investigate the role of lipoxin A4 (LXA4) in modulating renal fibrosis.
- To elucidate the mechanism by which LXA4 affects TGF-β1-induced fibrosis.
- To explore the involvement of microRNA let-7c in this process.
Main Methods:
- Cultured human proximal tubular epithelial (HK-2) cells were used to study gene expression.
- In vivo studies utilized a unilateral ureteral obstruction model of renal fibrosis.
- Bioinformatic analysis identified let-7c targets within the TGF-β1 signaling pathway.
- MicroRNA expression was modulated using mimics and inhibitors.
Main Results:
- LXA4 attenuated TGF-β1-induced expression of fibrotic markers (fibronectin, N-cadherin, thrombospondin, jagged-1) in HK-2 cells.
- LXA4 upregulated let-7c, while TGF-β1 suppressed it; LXA4's effect persisted after TGF-β1 stimulation.
- In vivo, an LXA4 analog induced let-7c upregulation in a renal fibrosis model.
- LXA4-induced let-7c inhibited TGF-β receptor type 1 expression and TGF-β1 response, mimicking antifibrotic effects.
- Fibrotic human renal biopsies showed upregulated let-7c target genes.
Conclusions:
- LXA4-mediated upregulation of let-7c suppresses TGF-β1-induced renal fibrosis.
- Let-7c acts as a key mediator in the antifibrotic effects of LXA4.
- Dysregulated expression of let-7c targets is observed in human renal fibrosis, highlighting therapeutic potential.
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