PLATELET-ACTIVATING-FACTOR STIMULATES GENE-EXPRESSION AND SYNTHESIS OF MATRIX PROTEINS IN CULTURED RAT AND HUMAN MESANGIAL CELLS - ROLE OF TGF-BETA

Platelet-activating factor (PAF) is a potent inflammatory mediator tha t participates in the pathogenesis of proteinuria and glomerular damag e. However, the role of this lipid in glomerular sclerosis remains unk nown. This study examines the effect of PAF on the regulation of extra cellular matrix proteins by rat and human mesangial cells. PAF increas ed in a dose-dependent manner the gene expression of fibronectin and t ype IV collagen, but not type I collagen. Moreover, an increase in cel l-associated and soluble fibronectin synthesis was also seen. These ef fects were abolished by BN52021 and WEB2086, two different PAF recepto r antagonists. Because transforming growth factor (TGF)-beta has been considered a profibrogenic cytokine, this study also evaluated whether PAF effects might be mediated by the production of endogenous TGF-bet a. PAF caused an increase in TGF-beta 1 mRNA expression (by a protein kinase C-dependent pathway) and TGF-beta activity. Moreover, PAF-induc ed fibronectin synthesis was totally abolished when an anti-TGF-beta-n eutralizing antibody was added to the culture medium, suggesting that PAF stimulates fibronectin synthesis, at least in part, through the in duction of TGF-beta. Addition of cycloheximide, a protein synthesis in hibitor, upregulated PAF-induced fibronectin mRNA expression but downr egulated PAF-induced TGF-beta 1 gene expression, suggesting the existe nce of different regulatory transcriptional factors of the two protein s. These results suggest that PAF may be implicated in matrix accumula tion during renal injury and therefore contribute to the pathogenesis of glomerulosclerosis.