Lipoxin A4 Inhibits Transition of Epithelial to Mesenchymal Cells in Proximal Tubules

Abstract

Background: Previous studies showed that connective tissue growth factor (CTGF)-induced proliferation of lung fibroblasts and production of chemokines in mesangial cells could be inhibited by lipoxin A₄ (LXA₄). It is speculated that LXA₄ could modulate the CTGF-induced epithelial to mesenchymal transition. Methods: The expressions of α-smooth muscle actin (α-SMA), E-cadherin, integrin-linked kinase (ILK), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K), Akt and Smad signaling were assessed by Western blot and/or real-time RT-PCR, and activation of Ras or ILK by activity assay, expressions of α-SMA and zonula occludens-1 by immunofluorescence assay in proximal tubular epithelial cells (HK-2). Results: Pretreatment of HK-2 cells with LXA₄ inhibited the morphological fibroblast-like changes and α-SMA expression induced by CTGF but not by transforming growth factor-β₁ (TGF-β₁). The expressions of E-cadherin and zonula occludens-1 reduced by CTGF but not by TGF-β₁ were increased by LXA₄. LXA₄ inhibited the expression and activity of ILK and activation of Ras, ERK1/2, PI3-K and Akt in HK-2 cells stimulated by CTGF. LXA₄ did not affect TGF-β₁-induced expression of ILK, Smad-2/3 phosphorylation and Smad-2’s binding to Smad-4 and subsequent nuclear translocation. Conclusion: LXA₄ inhibits the tubular epithelial to mesenchymal transition, initiated by CTGF but not by TGF-β₁, via downregulation of ILK, Ras/MEK/ERK1/2 and PI3-K/Akt-dependent signal pathway stimulated by CTGF.

Lipoxin A4-Induced Heme Oxygenase-1 Protects Cardiomyocytes against Hypoxia/Reoxygenation Injury via p38 MAPK Activation and Nrf2/ARE Complex

“…Our previous data also showed that LXA 4 slightly increased the phosphorylation of ERK but not PI3-K/Akt in renal mesangial cells and lung fibroblasts [20], [21], and slightly promoted the phosphorylation of ERK and p38 MAPK but not PI3-K in endothelial cells [22]. However, our data did not find LXA 4 activated ERK and PI3-K/Akt in renal tubular epithelial cells [23]. Pang H et al reported that LXA 4 blocked lipopolysaccharide-triggered ROS production in human umbilical vein, and the possible mechanism was through Nrf2 pathway [24].…”

Aspirin-triggered resolvin D1 inhibits TGF-β1-induced EMT through the inhibition of the mTOR pathway by reducing the expression of PKM2 and is closely linked to oxidative stress

“…A previous study (21) has shown that resolvin (Rv)D1 and RvD2 both suppressed TGF-β1-induced EMT, and RvD1 inhibited the TGF-β1-induced EMT through the lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) and G protein-coupled receptor 32 (GPR32) receptors by reducing the expression of ZEB1. Lipoxin A4 (LXA4), another mediator of resolution, has also been reported to inhibit the connective tissue growth factor (CTGF)-induced EMT process (27). Our results have shown that AT-RvD1 may also be useful in suppressing the EMT of lung cancer cells.…”

“…Several inflammatory mediators are released during these changes to the tumor microenvironment, leading to the progression and metastasis of the tumor (21). Specialized pro-resolving lipid mediators, such as lipoxin and resolvin, due to their involvement in the inhibitory process of EMT (21,27), have the ability to prevent excessive neutrophil trafficking to inflammation sites and thereby promote the recovery of damaged tissue (20,26,27). However, the role of AT-RvD1 remains unclear.…”

Lipoxin A 4 and benzo‐lipoxin A 4 attenuate experimental renal fibrosis

“…In glomerulonephritis, LXs reduce proteinuria, glomerular inflammation, and mesangial cell proliferation (11,14). LXA 4 regulates receptor tyrosine kinase activity in cultured endothelial cells and primary human mesangial cells, and there is evidence for a role for LXA 4 in maintaining renal epithelial integrity in the kidney and other tissues (15)(16)(17)(18). Native LXs undergo inactivation in vivo through prostaglandin dehydrogenase-mediated oxidation and reduction and -oxidation (19), and stable LX analogs have been synthesized.…”