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

Am J Pathol. 2005 Sep;167(3):683-94. doi: 10.1016/S0002-9440(10)62043-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects
  • Cell Extracts / pharmacology
  • Cells, Cultured
  • Epithelial Cells / cytology
  • Fibrosis / genetics*
  • Gene Expression / drug effects*
  • Glomerular Mesangium / chemistry
  • Glomerular Mesangium / metabolism*
  • Humans
  • Kidney Tubules, Proximal / cytology
  • Lipoxins / pharmacology*
  • Mesoderm / cytology
  • Oligonucleotide Array Sequence Analysis
  • Platelet-Derived Growth Factor / pharmacology*


  • Cell Extracts
  • Lipoxins
  • Platelet-Derived Growth Factor
  • lipoxin A4