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

Cunningham MA, Rondeau E, Chen X, Coughlin SR, Holdsworth SR, Tipping PG - J. Exp. Med. (2000)

Bottom Line: PAR-1-deficient (PAR-1(-/-)) mice, which have normal coagulation, also showed significant protection from crescentic GN compared with wild-type mice.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 3168 Victoria, Australia.

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.

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Functional parameters of injury in normal mice and mice with GN. Panels show serum creatinine (μmol/liter) and proteinuria (mg/24 h) in normal, nondiseased C57BL/6 mice (Normal, n = 6) and in C57BL/6 mice with GN treated with saline (WT GN), hirudin (WT GN + Hirudin), or TRAP (WT GN + TRAP) and in PAR-1−/− mice with GN treated with saline (PAR-1−/− GN) or TRAP (PAR-1−/− GN + TRAP).
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Figure 3: Functional parameters of injury in normal mice and mice with GN. Panels show serum creatinine (μmol/liter) and proteinuria (mg/24 h) in normal, nondiseased C57BL/6 mice (Normal, n = 6) and in C57BL/6 mice with GN treated with saline (WT GN), hirudin (WT GN + Hirudin), or TRAP (WT GN + TRAP) and in PAR-1−/− mice with GN treated with saline (PAR-1−/− GN) or TRAP (PAR-1−/− GN + TRAP).

Mentions: Administration of hirudin to block both the procoagulant and PAR-1–activating actions of thrombin afforded significant protection from the development of crescentic GN. Crescent formation and fibrin deposition are not observed in glomeruli of WT (Fig. 1 A) or PAR-1−/− mice (Fig. 1 B) before induction of GN. However, after sensitization to sheep globulin and administration of sheep anti–mouse GBM antibody, proliferative and crescentic GN was induced in WT mice (Fig. 1 C). Crescent formation occurred in 14 ± 3.1% of glomeruli. This was associated with prominent glomerular fibrin deposition (fibrin score 1.1 ± 0.1, normal = 0) and infiltration of CD4+ T cells (0.82 ± 0.07 c/gcs, normal = 0.01 ± 0.01 c/gcs) and macrophages (6.6 ± 0.6 c/gcs, normal = 0.02 ± 0.01 c/gcs) (Fig. 2), in keeping with the typical pathological features of a delayed-type hypersensitivity reaction. Previous studies have demonstrated that this model of GN results from a Th1-biased 29, MHC class II– 30 and CD4-dependent 31 immune response. The histological features of glomerular inflammation were associated with significant functional renal injury, indicated by increased serum creatinine (29 ± 2 μmol/liter; normal = 16 ± 2 μmol/liter; P < 0.001) and increased protein excretion in the urine (proteinuria 6.1 ± 0.5 mg/24 h; normal = 0.7 ± 0.1 mg/24 h; P < 0.001) (Fig. 3).


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

Cunningham MA, Rondeau E, Chen X, Coughlin SR, Holdsworth SR, Tipping PG - J. Exp. Med. (2000)

Functional parameters of injury in normal mice and mice with GN. Panels show serum creatinine (μmol/liter) and proteinuria (mg/24 h) in normal, nondiseased C57BL/6 mice (Normal, n = 6) and in C57BL/6 mice with GN treated with saline (WT GN), hirudin (WT GN + Hirudin), or TRAP (WT GN + TRAP) and in PAR-1−/− mice with GN treated with saline (PAR-1−/− GN) or TRAP (PAR-1−/− GN + TRAP).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195821&req=5

Figure 3: Functional parameters of injury in normal mice and mice with GN. Panels show serum creatinine (μmol/liter) and proteinuria (mg/24 h) in normal, nondiseased C57BL/6 mice (Normal, n = 6) and in C57BL/6 mice with GN treated with saline (WT GN), hirudin (WT GN + Hirudin), or TRAP (WT GN + TRAP) and in PAR-1−/− mice with GN treated with saline (PAR-1−/− GN) or TRAP (PAR-1−/− GN + TRAP).
Mentions: Administration of hirudin to block both the procoagulant and PAR-1–activating actions of thrombin afforded significant protection from the development of crescentic GN. Crescent formation and fibrin deposition are not observed in glomeruli of WT (Fig. 1 A) or PAR-1−/− mice (Fig. 1 B) before induction of GN. However, after sensitization to sheep globulin and administration of sheep anti–mouse GBM antibody, proliferative and crescentic GN was induced in WT mice (Fig. 1 C). Crescent formation occurred in 14 ± 3.1% of glomeruli. This was associated with prominent glomerular fibrin deposition (fibrin score 1.1 ± 0.1, normal = 0) and infiltration of CD4+ T cells (0.82 ± 0.07 c/gcs, normal = 0.01 ± 0.01 c/gcs) and macrophages (6.6 ± 0.6 c/gcs, normal = 0.02 ± 0.01 c/gcs) (Fig. 2), in keeping with the typical pathological features of a delayed-type hypersensitivity reaction. Previous studies have demonstrated that this model of GN results from a Th1-biased 29, MHC class II– 30 and CD4-dependent 31 immune response. The histological features of glomerular inflammation were associated with significant functional renal injury, indicated by increased serum creatinine (29 ± 2 μmol/liter; normal = 16 ± 2 μmol/liter; P < 0.001) and increased protein excretion in the urine (proteinuria 6.1 ± 0.5 mg/24 h; normal = 0.7 ± 0.1 mg/24 h; P < 0.001) (Fig. 3).

Bottom Line: PAR-1-deficient (PAR-1(-/-)) mice, which have normal coagulation, also showed significant protection from crescentic GN compared with wild-type mice.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 3168 Victoria, Australia.

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.

Show MeSH
Related in: MedlinePlus