Glomerular fibrinolytic activity in anti-GBM glomerulonephritis in rabbits.
Fibrin is an important mediator of injury in severe proliferative forms of glomerulonephritis (GN). Normal glomeruli express fibrinolytic activity, which may protect against the injurious effects of fibrin deposition. Changes in glomerular fibrinolytic activity (GFA) may play an important role in modulating fibrin accumulation in GN. To study the changes in GFA associated with fibrin deposition in GN, autologous phase anti-glomerular basement antibody initiated GN (anti-GBM GN) was studied in rabbits. Net GFA was significantly reduced in association with glomerular fibrin deposition (1.3 +/- 0.8 ng fibrin lysed/10(3) glomeruli/2 hr, normal 57.1 +/- 25.4 ng fibrin lysed/10(3) glomeruli/2 hr, P < 0.02). Reduced GFA in fibrin associated GN was associated with decreased expression of tissue type plasminogen activator (tPA) and increased expression of plasminogen activator inhibitor type-1 (PAI-1) and glomerular macrophage infiltration. In a fibrin independent model of anti-GBM induced GN (heterologous phase), with equivalent injury (proteinuria), net GFA was increased (174 +/- 64 ng fibrin lysed/10(3) glomeruli/2 hr). This was associated with increased tPA and uPA, and decreased PAI-1 in the absence of significant macrophage infiltration. These studies demonstrate that fibrin deposition in GN is associated with a net reduction of GFA, attributable to reduced expression of plasminogen activators and augmentation of PAI-1. Reduction of GFA may potentiate glomerular fibrin deposition and consequent glomerular injury. The association between glomerular macrophage influx and reduction in GFA suggests that this change may be directed by macrophages.
Malliaros
J
J
Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Holdsworth
S R
SR
Wojta
J
J
Erlich
J
J
Tipping
P G
PG
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D000941:Antigens / Q000378:metabolism; D001485:Basement Membrane / Q000276:immunology; D015536:Down-Regulation; D005342:Fibrinolysis; D005921:Glomerulonephritis / Q000209:etiology / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011817:Rabbits; D010959:Tissue Plasminogen Activator / Q000276:immunology / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D000906:Antibodies; D000941:Antigens; D017395:Plasminogen Activator Inhibitor 1; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator