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Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic
B Lelongt1, S Bengatta, M Delauche
1Institut National de la Santé et de la Recherche Médicale, Unité 489, Hôpital Tenon and Université Pierre et Marie Curie (Paris 6), 75020 Paris, France. brigitte.lelongt@tnn.ap-hop-paris.fr
Abstract:
Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies. To investigate its role, we used a genetic approach. Adult MMP9-deficient (MMP9(-/)-) mice showed normal renal histology and function at 3 mo. We investigated the susceptibility of 3-mo-old mice to the accelerated model of anti-glomerular basement membrane nephritis, in which fibrin is an important mediator of glomerular injury and renal impairment. Unexpectedly, nephritis was more severe in MMP9(-/)- than in control mice, as attested by levels of serum creatinine and albuminuria, and the extent of crescents and fibrin deposits. Circulating or deposited immunoglobulin G, interleukin (IL)-1beta, or IL-10 were the same in MMP9(-/-) and MMP9(+/+) mice. However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli. These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.
Insights
Matrix metalloproteinase (MMP)9 deficiency unexpectedly worsened anti-glomerular basement membrane nephritis in mice. MMP9 normally degrades fibrin, preventing its accumulation and protecting against glomerular injury.
Area of Science:
- Nephrology
- Immunology
- Biochemistry
Background:
- Matrix metalloproteinase (MMP)9 is elevated in various kidney diseases.
- Its precise role in nephropathies, particularly anti-glomerular basement membrane nephritis, remains unclear.
Purpose of the Study:
- To investigate the role of MMP9 in the pathogenesis of anti-glomerular basement membrane nephritis using a genetic approach.
- To determine if MMP9 deficiency influences the severity of glomerular injury mediated by fibrin.
Main Methods:
- Utilized a genetic approach with adult MMP9-deficient (MMP9(-/-)) mice.
- Induced an accelerated model of anti-glomerular basement membrane nephritis.
- Assessed renal histology, function (serum creatinine, albuminuria), and fibrin deposition.
Main Results:
- MMP9(-/-) mice exhibited more severe nephritis than control (MMP9(+/+)) mice.
- Increased serum creatinine, albuminuria, glomerular crescents, and fibrin deposition were observed in MMP9(-/-) mice.
- Fibrin accumulation in glomeruli was significantly higher in MMP9(-/-) mice, indicating fibrin is a critical substrate for MMP9.
Conclusions:
- MMP9 plays a protective role in the development of fibrin-induced glomerular lesions.
- MMP9 is essential for degrading fibrin, thereby preventing its pathological accumulation in the glomeruli during nephritis.