title: Lipoxin A4 modifies platelet-derived growth factor-induced pro-fibrotic gene expression in human renal mesangial cells.
abstract: Lipoxins (LXs), endogenously produced eicosanoids, possess potent anti-inflammatory, pro-resolution bioactivities. We investigated the potential of LXA(4) (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 pro-fibrotic cytokines and matrix-associated genes induced in response to PDGF. LXA(4) modulated the expression of many PDGF-induced genes, including transforming growth factor-beta1, 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 pro-fibrotic phenotype. Interestingly, supernatant from cells pre-exposed to LXA(4) and PDGF did not induce these effects. These results suggest a novel role for LXA(4) as a potent modulator of matrix accumulation and pro-fibrotic change and suggest a potential protective role in progressive renal disease.
authors.affiliation: Department of Medicine and Therapeutics, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors.forename: Karen
authors.initials: K
authors.lastname: Rodgers
authors.forename: Blaithin
authors.initials: B
authors.lastname: McMahon
authors.forename: Derick
authors.initials: D
authors.lastname: Mitchell
authors.forename: Denise
authors.initials: D
authors.lastname: Sadlier
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002457:Cell Extracts / Q000494:pharmacology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology; D005355:Fibrosis / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology; D044045:Lipoxins / Q000494:pharmacology*; D008648:Mesoderm / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*
chemical_list: D002457:Cell Extracts; D044045:Lipoxins; D010982:Platelet-Derived Growth Factor; C040527:lipoxin A4