Plasminogen activator inhibitor-1 is a significant determinant of renal injury in experimental crescentic
A Richard Kitching1, Yao Z Kong, Xiao Ru Huang
1Centre for Inflammatory Diseases, and Department of Medicine, Monash Medical Centre, Monash University, Clayton, Victoria, Australia.
Insights
Plasminogen activator inhibitor-1 (PAI-1) significantly impacts crescentic glomerulonephritis. Reduced PAI-1 levels lessened kidney injury and fibrin deposition, while increased PAI-1 exacerbated these conditions.
Area of Science:
- Nephrology
- Immunology
- Hematology
Background:
- Crescentic glomerulonephritis involves glomerular fibrin deposition and is fibrin-dependent.
- The fibrinolytic system counterbalances coagulation-driven fibrin deposition.
- Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis and influences inflammation and matrix deposition.
Purpose of the Study:
- To investigate the role of Plasminogen activator inhibitor-1 (PAI-1) levels in determining the severity of crescentic glomerulonephritis.
- To assess the impact of PAI-1 deficiency and overexpression on kidney injury markers.
Main Methods:
- Accelerated anti-glomerular basement membrane glomerulonephritis was induced in mice.
- Studies utilized PAI-1 deficient (PAI-1 -/-), heterozygous (PAI-1 +/-), and PAI-1 overexpressing (PAI-1 tg) mouse models.
- Kidney tissues were analyzed for glomerular crescents, fibrin deposition, leukocyte infiltration, and collagen accumulation at 14 and 28 days.
Main Results:
- PAI-1 -/- mice exhibited significantly reduced glomerular crescents, fibrin deposition, leukocyte infiltration, and renal collagen compared to controls.
- PAI-1 tg mice showed increased glomerular crescent formation, fibrin deposition, leukocyte infiltration, and renal collagen at both time points.
- These findings indicate PAI-1 is a critical factor in disease progression.
Conclusions:
- Plasminogen activator inhibitor-1 (PAI-1) is a key determinant of glomerular fibrin deposition and renal injury in crescentic glomerulonephritis.
- Modulating PAI-1 levels offers a potential therapeutic strategy for managing this kidney disease.
Abstract:
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.
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