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 (LXA 4 ) attenuated TGF-b1-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-b1 suppressed expression of let-7c. In cells pretreated with LXA 4 , upregulation of let-7c persisted despite subsequent stimulation with TGF-b1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA 4 analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-b1 signaling pathway, including the TGF-b receptor type 1. Consistent with this, LXA 4 -induced upregulation of let-7c inhibited both the expression of TGF-b receptor type 1 and the response to TGF-b1. Overexpression of let-7c mimicked the antifibrotic effects of LXA 4 in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA 4 . 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 LXA 4 -mediated upregulation of let-7c suppresses TGF-b1-induced fibrosis and that expression of let7c targets is dysregulated in human renal fibrosis.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Several molecules were proposed to be involved in the profibrotic switch of fibroblasts (or pericytes) during renal fibrosis, including the Wnt signaling pathway (e.g., Wnt4, LRP-6, and DKK-1) (183,184), oxidative stress and NADPH oxidase (39,88,185), integrins including aV integrin (186), Rheb/mTORC1 signaling (187) as well as lipid mediators, including prostaglandins and their receptors like EP4 (188,189), prostacyclins (190), or lipoxins (191,192).…”

Transforming Growth Factor β1 (TGF-β1) Enhances Expression of Profibrotic Genes through a Novel Signaling Cascade and MicroRNAs in Renal Mesangial Cells

“…Recently, it was found that under normal conditions, let-7 maintains low levels of TGF-␤R1 expression in human umbilical vein endothelial cells and in adult human liver cells (30,31). In addition, in tubular epithelial cells, lipoxins were shown to down-regulate TGF-␤R1-induced fibrosis by up-regulating let-7c (32). Another recent paper also showed that let-7b targets TGF-␤R1 related to kidney fibrosis (33).…”

“…1, A-C). Recent reports have identified TGF-␤R1 as a target of let-7c and let-7b in renal cells (30,32,33). Interestingly, computational analysis using Target Scan software identified TGF-␤R1 as a potential profibrotic target of not only let-7b but also the other two miRNAs, miR-130b and miR-30e*.…”

“…TGF-␤1 Induces TGF-␤R1 Expression via Down-regulation of miR-130b and let-7b-It was recently reported that let-7c and let-7b directly bind and target the TGF-␤R1 3Ј-UTR in renal epithelial cells, leading to an attenuation of downstream genes associated with renal fibrosis (32,33). let-7 was also shown to target TGF-␤R1 in adult human liver cells to regulate human liver development (30).…”

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

“…[33][34][35] More recently, LXA 4 exhibited antifibrotic properties by upregulation of let-7c expression in renal fibrosis. 36 However, whether LXA 4 augments AFC through a particular miRNA in LPS-induced ALI, and if so, what the underlying mechanisms are remain unclear.…”