Plasminogen activators and their inhibitor synthesized by human mesangial cells and other cell types
The plasminogen activator synthesized by human mesangial cells was identified as tissue-type plasminogen activator (t-PA). Glomerular epithelial cells synthesized t-PA and urokinase (u-PA). Both mesangial cells and glomerular epithelial cells synthesized plasminogen activator inhibitor-1 (PAI-1) into culture supernatant. In this study experimental techniques were developed to allow quantification of matrix-associated PAI-1. PAI-1 associated with the matrix of mesangial cells was less than 1% of the total PAI-1 synthesized by the cells. Similar amounts were detected in the matrix of human umbilical vein endothelial cells and Hep G2 cells. When cultured in the presence of transforming growth factor- (TGF-), PAI-1 synthesized by mesangial cells was significantly increased and this up-regulation was shown to occur at the mRNA level. PAI-1 associated with the matrix of mesangial cells also significantly increased, though matrix-associated PAI-1 still constituted less than 1% of the total PAI-1 synthesized by the cells. TGF- stimulated the synthesis of PAI-1 by whole glomeruli, epithelial cells and epithelial-mesangial cell co-cultures, while decreasing their overall plasminogen activator synthesis. When cultured in the presence of platelet-derived growth factor-BB (PDGF-BB) there was no effect on either PA or PAI-1 synthesized by the glomerular cells examined. TGF- has been implicated in the development of glomerulonephritis via an effect on matrix production. Our results suggest tht TGF- also plays a role in the proteolytic balance within the glomerulus, leading to an environment favouring its deposition.