Affiliation:
1. Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 3168 Victoria, Australia
2. Institut National de la Santé et de la Recherche Médicale (INSERM) U489, Hospital Tenon, Paris 75970, France
3. Cardiovascular Research Institute, University of California, San Francisco, California 94145-0130
Abstract
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.
Publisher
Rockefeller University Press
Subject
Immunology,Immunology and Allergy
Reference34 articles.
1. Requirement for binding of catalytically active factor VIIa in tissue factor–dependent experimental metastasis;Mueller;J. Clin. Invest.,1998
2. Effector cell protease receptor-1 is a vascular receptor for coagulation factor Xa;Nicholson;J. Biol. Chem.,1996
3. Thrombin and trypsin-induced Ca(2+) mobilization in human T cell lines through interaction with different protease-activated receptors;Mari;FASEB (Fed. Am. Soc. Exp. Biol.) J.,1996
4. Protein C prevents the coagulopathic and lethal effects of E. coli infusion in the baboon;Taylor;J. Clin. Invest.,1987
5. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody;Taylor;Circ. Shock.,1991
Cited by
195 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献