Dual effects of angiotensin II on the plasminogen/plasmin system in rat mesangial cells

Abstract

Previous studies indicate that angiotensin II (Ang II) stimulates extracellular matrix synthesis through induction of transforming growth factor-beta (TGF-beta) expression. Here we investigate Ang II effects on the plasmin protease system. Plasmin both degrades extracellular matrix itself and activates metalloproteinases which then degrade collagens. Plasmin production is determined by the balance between plasminogen activators (PA) and their inhibitors (PAI-1,2). The data presented here indicate that Ang II treatment of mesangial cells in culture markedly increases PAI-1 gene transcription and PAI-1 mRNA levels but does not change the half life of PAI-1 mRNA. Increased PAI-1 protein was detected 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 prolonged effect of Ang II on PAI-1 protein synthesis was markedly diminished. Thus, Ang II acts both through rapid, direct transcriptional up-regulation of the PAI-1 gene and through induction of TGF-beta, providing sustained changes in the PAI-1/PA system, which would favor extracellular 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.

Addition of the Antioxidant Probucol to Angiotensin II Type I Receptor Antagonist Arrests Progressive Mesangioproliferative Glomerulonephritis in the Rat

“…These clinical and experimental in vivo studies have strongly suggested that the renoprotective effect of these antihypertensive agents results from not simply the inhibition of its hemodynamic action but also blockade of its hemodynamicindependent actions. In fact, many studies, including our previous in vitro studies, have disclosed the mechanisms and the role of Ang II-induced ECM deposition through mesangial cells (11)(12)(13). Ang II stimulates ECM synthesis through the induction of TGF-␤1 expression in cultured rat glomerular mesangial cells (11) and affects the plasminogen activator/ plasminogen activator inhibitor-1 system to result in accelerated deposition of ECM (12), which constitutes evidence that Ang II can act as a potent fibrotic molecule independent of its effects on BP.…”

Screening and Identification of the Up-Regulated Genes in Human Mesangial Cells Exposed to Angiotensin II.

“…Ang II induced the synthesis and secretion of FN, and of type I and III collagen from MC (7,8,12). In our previous study, Ang II was dramatically increased in the local renal tissue of puromycin nephropathy rats, and this increase was related with the progression of puromycin nephropathy.…”

Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen

“…Both Ang II (or its hexapeptide metabolite, Ang IV) and aldosterone increase PAI-1 expression in a variety of cell types, including astrocytes, 35 endothelial cells, 4 vascular smooth muscle cells, 36 proximal tubular epithelial cells, 37 and mesangial cells. 38 Systemic infusion of Ang II increases vascular, renal, and hepatic PAI-1 expression in rats, 39 whereas treatment of animals with ACE inhibitors, AT 1 receptor antagonists, or aldosterone receptor antagonists decreases tissue PAI-1 expression. 15,40 Ang II stimulates PAI-1 expression through a serum-inducible element localized to a sequence between Ϫ47 and Ϫ38 bp in the PAI-1 promoter.…”