Glomerular fibrinolytic activity in anti-GBM glomerulonephritis in rabbits

Abstract

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.

Protease Nexin-1, tPA, and PAI-1 are Upregulated in Cryoglobulinemic Membranoproliferative Glomerulonephritis

“…6 Upregulation of PAI-1 in diseased glomeruli has also been well documented in experimental immune complex-mediated glomerulonephritis 4,5,19,20 and in human glomerulonephritis 21 and was observed in the mesangium of TSLP transgenic mice. PAI-1 can be induced by TGF-␤1 in rodent kidneys and in cultured mesangial cells.…”

Renal expression of tissue factor pathway inhibitor and evidence for a role in crescentic glomerulonephritis in rabbits.

“…Renal histology was assessed on tissue sections fixed in Bouin's fixative, stained with silver methenamine/trichrome. Other indices of injury at these time points in this model, including glomerular crescent formation, fibrin deposition, proteinuria, macrophage infiltration, tissue factor expression and changes in fibrinolytic activity have previously extensively characterized in this model (27,28).…”

“…GFD was assessed in a blinded protocol. Only glomeruli cut in or near the equatorial cross section were included and the extent of immunofluorescence staining in glomeruli scored on a scale from 0 (normal) to ϩ 3 (fibrin deposition involving greater than two thirds of the glomerular cross section) as previously described (17,27,31). At least 50 glomeruli per animal were scored.…”

“…Horse antirabbit GBM antibody was prepared as previously described (27,28). GN was induced by intravenous administration of horse anti-rabbit GBM globulin (25 mg/kg) to rabbits, presensitized to horse globulin 5 d earlier by subcutaneous injection of horse globulin (4 mg) in Freund's complete adjuvant (CSL).…”

Cryoglobulinemic glomerulonephritis — lessons from animal models

“…Number of plasminogen activator inhibitors, such as protease nexin-1 (PN-1) and plasminogen activators inhibitor PAI-1, among their complex activities, they inhibit generation of plasmin. Several studies demonstrated decreased PA activity and plasmin activity in glomeruli in various forms of experimental injury that resulted in mesangial matrix expansion [52,53]. Increased levels of PAI-1 have been observed in various forms of kidney diseases leading to renal fibrosis [53,54].…”