J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/03/963/06 $2.00
Volume 185, Number 5, March 3, 1997 963-968

BRIEF DEFINITIVE REPORT:
Plasminogen and Plasminogen Activators Protect against Renal Injury in Crescentic Glomerulonephritis

By A. Richard Kitching,^* Stephen R. Holdsworth,^* Victoria A. Ploplis,^§ Edward F. Plow,^§ Désiré Collen, Peter Carmeliet, and Peter G. Tipping^*

From the ^* Center for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 3168, Victoria, Australia;  Center for Transgene Technology and Gene Therapy, Vlaams Interuniversitair Instituut voor Biotechnologie, B-3000 Leuven, Belgium; and ^§ Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland, Ohio 44195

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.

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