Lipoxin A4 modifies platelet-derived growth factor-induced profibrotic gene expression in human renal mesangial cells

Lipoxins (LXs), endogenously produced eicosanoids, possess potent anti-inflammatory, proresolution bioactivities. We investigated the potential of LXA₄ (1 to 10 nmol/L) to modify the effects of platelet-derived growth factor (PDGF)-induced gene expression in human renal mesangial cells (hMCs). Using oligonucleotide microarray analysis we profiled profibrotic cytokines and matrix-associated genes induced in response to PDGF. LXA ₄ modulated the expression of many PDGF-induced genes, including transforming growth factor-β1, fibronectin, thrombospondin, matrix metalloproteinase 1, and several collagens. Analysis of both transcript and protein levels confirmed these findings. Because the activated glomerulus is frequently a source of injurious mediators that contribute to tubulointerstitial damage, we investigated the effect of hMC-secreted products on the integrity of renal proximal tubular epithelial cells using an in vitro model of progressive renal disease. Cell supernatant from PDGF-stimulated hMCs caused morphological and genetic changes in proximal tubular epithelial cells, consistent with a profibrotic phenotype. Interestingly, supernatant from cells pre-exposed to LXA₄ and PDGF did not induce these effects. These results suggest a novel role for LXA₄ as a potent modulator of matrix accumulation and profibrotic change and suggest a potential protective role in progressive renal disease.