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PMID: 16127149 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The American journal of pathology ·Vol. 167 ·No. 3 ·2005-09-00 ·Pages 683-94

Rodgers K, McMahon B, Mitchell D, Sadlier D, Godson C

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.

MeSH Terms
Cell Differentiation/drug effects Cell Extracts/pharmacology Cells, Cultured Epithelial Cells/cytology Fibrosis/genetics Gene Expression/drug effects Glomerular Mesangium/chemistry,metabolism Humans Kidney Tubules, Proximal/cytology Lipoxins/pharmacology Mesoderm/cytology Oligonucleotide Array Sequence Analysis Platelet-Derived Growth Factor/pharmacology
Chemicals
Cell Extracts Lipoxins Platelet-Derived Growth Factor lipoxin A4
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Rodgers Karen
Department of Medicine and Therapeutics, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
McMahon Blaithin
Mitchell Derick
Sadlier Denise
Godson Catherine
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)62043-3
Published
2005-09-00
Pages
683-94
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1698722
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1016/S0002-9440(10)62043-3 PMC Full Text View journal details
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