The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/2/455/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 3, February 7, 2000 455-462

Original Article

Protease-activated Receptor 1 Mediates Thrombin-dependent, Cell-mediated Renal Inflammation in Crescentic Glomerulonephritis

Malcolm A. Cunninghama, Eric Rondeaub, Xin Chenb, Shaun R. Coughlinc, Stephen R. Holdswortha, and Peter G. Tippinga
a Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 3168 Victoria, Australia
b Institut National de la Santé et de la Recherche Médicale (INSERM) U489, Hospital Tenon, Paris 75970, France
c Cardiovascular Research Institute, University of California, San Francisco, California 94145-0130

Correspondence to: Peter G. Tipping, Monash University, Dept. of Medicine, Monash Medical Centre, 246 Clayton Rd., Clayton, 3168 Victoria, Australia. Tel:61-3-9594-5547 Fax:61-3-9594-4279 E-mail:peter.tipping{at}med.monash.edu.au.

Protease-activated receptor (PAR)-1 is a cellular receptor for thrombin that is activated after proteolytic cleavage. The contribution of PAR-1 to inflammatory cell–mediated renal injury was assessed in murine crescentic glomerulonephritis (GN). A pivotal role for thrombin in this model was demonstrated by the capacity of hirudin, a selective thrombin antagonist, to attenuate renal injury. Compared with control treatment, hirudin significantly reduced glomerular crescent formation, T cell and macrophage infiltration, fibrin deposition, and elevated serum creatinine, which are prominent features of GN. PAR-1–deficient (PAR-1-/-) mice, which have normal coagulation, also showed significant protection from crescentic GN compared with wild-type mice. The reductions in crescent formation, inflammatory cell infiltration, and serum creatinine were similar in PAR-1-/- and hirudin-treated mice, but hirudin afforded significantly greater protection from fibrin deposition. Treatment of wild-type mice with a selective PAR-1–activating peptide (TRAP) augmented histological and functional indices of GN, but TRAP treatment did not alter the severity of GN in PAR-/- mice. These results indicate that activation of PAR-1 by thrombin or TRAP amplifies crescentic GN. Thus, in addition to its procoagulant role, thrombin has proinflammatory, PAR-1–dependent effects that augment inflammatory renal injury.

Key Words: coagulation, kidney, cell-mediated immunity, hirudin, in vivo


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