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(American Journal of Pathology. 2005;167:683-694.)
© 2005 American Society for Investigative Pathology

Lipoxin A4 Modifies Platelet-Derived Growth Factor-Induced Profibrotic Gene Expression in Human Renal Mesangial Cells

Karen Rodgers, Blaithin McMahon, Derick Mitchell, Denise Sadlier and Catherine Godson

From the Department of Medicine and Therapeutics, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin; and The Dublin Molecular Medicine Centre, Dublin, Ireland

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. LXA4 modulated the expression of many PDGF-induced genes, including transforming growth factor-ß1, 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.




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