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Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis
A R Kitching1, S R Holdsworth, V A Ploplis
1Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Victoria, Australia.
Insights
Plasminogen protects kidneys from inflammatory injury. Its deficiency, or that of tissue-type plasminogen activator (tPA), worsens crescentic glomerulonephritis (GN) in mice, highlighting their crucial protective roles.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- The plasminogen/plasmin system regulates fibrin and matrix protein accumulation, influencing inflammatory disease outcomes.
- Fibrin and matrix protein deposition are key mediators of glomerular injury and renal impairment in crescentic glomerulonephritis (GN).
Purpose of the Study:
- To investigate the role of plasminogen and its activators in the pathogenesis of inflammatory glomerular injury.
- To elucidate the specific contributions of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) in GN.
Main Methods:
- Induction of crescentic glomerulonephritis (GN) in genetically modified mice lacking plasminogen, tPA, uPA, or uPA receptor.
- Assessment of functional and histological parameters of glomerular injury and inflammation.
Main Results:
- Plasminogen deficiency led to severe exacerbation of glomerular injury and renal impairment.
- Combined deficiency of tPA and uPA, or deficiency of tPA alone, significantly worsened GN.
- uPA deficiency showed a trend towards reduced macrophage infiltration but did not exacerbate disease.
- uPA receptor deficiency had no significant effect on GN expression.
Conclusions:
- Plasminogen is essential for protecting the glomerulus against acute inflammatory injury.
- Tissue-type plasminogen activator (tPA) is the primary plasminogen activator conferring protection in GN.
- The plasminogen system, particularly tPA, represents a potential therapeutic target for inflammatory kidney diseases.
Abstract:
The plasminogen/plasmin system has the potential to affect the outcome of inflammatory diseases by regulating accumulation of fibrin and other matrix proteins. In human and experimental crescentic glomerulonephritis (GN), fibrin is an important mediator of glomerular injury and renal impairment. Glomerular deposition of matrix proteins is a feature of progressive disease. To study the role of plasminogen and plasminogen activators in the development of inflammatory glomerular injury, GN was induced in mice in which the genes for these proteins had been disrupted by homologous recombination. Deficiency of plasminogen or combined deficiency of tissue type plasminogen activator (tPA) and urokinase type plasminogen activator (uPA) was associated with severe functional and histological exacerbation of glomerular injury. Deficiency of tPA, the predominant plasminogen activator expressed in glomeruli, also exacerbated disease. uPA deficiency reduced glomerular macrophage infiltration and did not significantly exacerbate disease. uPA receptor deficiency did not effect the expression of GN. These studies demonstrate that plasminogen plays an important role in protecting the glomerulus from acute inflammatory injury and that tPA is the major protective plasminogen activator.