Crescentic
glomerulonephritis is characterized by glomerular
fibrin deposition, and experimental crescentic
glomerulonephritis has been shown to be
fibrin-dependent. Net
fibrin deposition is a balance between activation of the coagulation system causing glomerular
fibrin deposition and
fibrin removal by the
plasminogen-
plasmin (fibrinolytic) system.
Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis by inhibiting
plasminogen activators and has effects on leukocyte recruitment and matrix deposition. To test the hypothesis that the presence of
PAI-1 and its levels were a determinant of injury in crescentic
glomerulonephritis, accelerated anti-glomerular basement membrane
glomerulonephritis was induced in mice genetically deficient in
PAI-1 (PAI-1 -/-),
PAI-1 heterozygotes (PAI-1 +/-), and mice engineered to overexpress
PAI-1 (PAI-1 tg). Compared with strain-matched genetically normal animals,
PAI-1 -/- mice with
glomerulonephritis developed fewer glomerular crescents, less glomerular
fibrin deposition, fewer infiltrating leukocytes, and less renal
collagen accumulation at day 14 of disease. The reduction in disease persisted at day 28, when injury had become more established. In contrast, mice overexpressing the
PAI-1 gene (PAI-1 tg), that have basal plasma and renal
PAI-1 levels several times, normal developed increased glomerular crescent formation, more glomerular
fibrin deposition, increased numbers of infiltrating leukocytes, and more renal
collagen at both time points. These studies demonstrate that
PAI-1 is a determinant of glomerular
fibrin deposition and renal injury in crescentic
glomerulonephritis.