Protease-Activated Receptor 1 Mediates Thrombin-Dependent, Cell-Mediated Renal Inflammation in Crescentic Glomerulonephritis

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  • Malcolm A. Cunningham
    aCentre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 3168 Victoria, Australia
  • Eric Rondeau
    bInstitut National de la Santé et de la Recherche Médicale (INSERM) U489, Hospital Tenon, Paris 75970, France
  • Xin Chen
    bInstitut National de la Santé et de la Recherche Médicale (INSERM) U489, Hospital Tenon, Paris 75970, France
  • Shaun R. Coughlin
    cCardiovascular Research Institute, University of California, San Francisco, California 94145-0130
  • Stephen R. Holdsworth
    aCentre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 3168 Victoria, Australia
  • Peter G. Tipping
    aCentre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 3168 Victoria, Australia

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<jats:p>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.</jats:p>

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