Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis

Protease-activated receptor (PAR)-1 is a cellular receptor for thrombin tha t is activated after proteolytic cleavage. The contribution of PAR-1 to inf lammatory cell-mediated renal injury was assessed in murine crescentic glom erulonephritis (GN). A pivotal role for thrombin in this model tvas demonst rated by the capacity of hirudin, a selective thrombin antagonist, to atten uate renal injury. Compared with control treatment, hirudin significantly r educed glomerular crescent formation, T cell and macrophage infiltration, f ibrin deposition, and elevated serum creatinine, which are prominent featur es of GN. PAR-1-defcient (PAR-1(-/-)) mice, which have normal coagulation, also showed significant protection from crescentic GN compared with wild-ty pe mice. The reductions in crescent formation, inflammatory cell infiltrati on, and serum creatinine were similar in PAR-1(-/-) and hirudin-treated mic e, but hirudin afforded significantly greater protection from fibrin deposi tion. Treatment of wild-type mice with a selective PAR-1-activating peptide (TRAP) augmented histological and functional indices of GN, but TRAP treat ment did not alter the severity of GN in PAR(-/-) mice. These results indic ate that activation of PAR-1 by thrombin or TRAP amplifies crescentic GN. T hus, in addition to its procoagulant role, thrombin has proinflammatory, PA R-1-dependent effects that augment inflammatory renal injury.