Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity.
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.
Lelongt
B
B
Institut 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
Bengatta
S
S
Delauche
M
M
Lund
L R
LR
Werb
Z
Z
Ronco
P M
PM
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology* / Q000473:pathology; D001485:Basement Membrane / Q000276:immunology; D005337:Fibrin / Q000378:metabolism*; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D011507:Proteinuria
D005337:Fibrin; D020780:Matrix Metalloproteinase 9