The Journal of Experimental Medicine
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Published online 2 April 2001.
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© The Rockefeller University Press, 0022-1007/2001/4/793/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 7, April 2, 2001 793-802

Original Article

Matrix Metalloproteinase 9 Protects Mice from Anti–Glomerular Basement Membrane Nephritis through Its Fibrinolytic Activity

Brigitte Lelongta, Soraya Bengattaa, Madeleine Delauchea, Leif R. Lundb, Zena Werbc, and Pierre M. Roncoa

a 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
b Finsen Laboratory, DK-2100 Copenhagen, Denmark
c Department of Anatomy, University of California at San Francisco, San Francisco, California 94143
Unité INSERM 489, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France.33-1-56-01-62-1733-1-56-01-65-14

brigitte.lelongt{at}tnn.ap-hop-paris.fr

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)-1β, 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.

Key Words: matrix metalloproteinase • kidney • fibrin • crescent • proteinuria

Abbreviations used in this paper: GBM, glomerular basement membrane; MMP, matrix metalloproteinase; PAS, periodic acid-Schiff; TIMP, tissue inhibitor of metalloproteinase; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator.

© 2001 The Rockefeller University Press


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