DUAL EFFECTS OF ANGIOTENSIN-II ON THE PLASMINOGEN PLASMIN SYSTEM IN RAT MESANGIAL CELLS/

Previous studies indicate that angiotensin II (Ang II) stimulates extr acellular matrix synthesis through induction of transforming growth fa ctor-beta (TGF-beta) expression. Here we investigate Ang II effects on the plasmin protease system. Plasmin both degrades extracellular matr ix itself and activates metalloproteinases which then degrade collagen s. Plasmin production is determined by the balance between plasminogen activators (PA) and their inhibitors (PAI-1,2). The data presented he re indicate that Ang II treatment of mesangial cells in culture marked ly increases PAI-1 gene transcription and PAI-1 mRNA levels but does n ot change the half life of PAI-1 mRNA. Increased PAI-1 protein was det ected 24 hours after Ang II stimulation with a concomitant decrease of PA activity. To determine whether these effects were mediated by TGF- beta, cells were coincubated with Ang II and neutralizing antibody to TGF-beta. Induction of PAI-1 at four hours was not altered but the pro longed effect of Ang II on PAI-1 protein synthesis was markedly dimini shed. Thus, Ang II acts both through rapid, direct transcriptional up- regulation of the PAI-1 gene and through induction of TGF-beta, provid ing sustained changes in the PAI-1/PA system, which would favor extrac ellular matrix accumulation by inhibiting turnover. These data provide further evidence that Ang II can act as a potent fibrogenic molecule independent of its effects on blood pressure.