Protease-activated receptor-2 augments experimental crescentic glomerulonephritis.
Protease-activated receptor-2 (PAR-2) is a cellular receptor expressed prominently on epithelial, mesangial, and endothelial cells in the kidney and on macrophages. PAR-2 is activated by serine proteases such as trypsin, tryptase, and coagulation factors VIIa and Xa. It induces pleiotropic effects including vasodilatation, increasing plasminogen activator inhibitor (PAI-1) expression, mesangial cell proliferation, and cytokine production by macrophages. The role of PAR-2 in renal inflammation was studied in antiglomerular basement membrane antibody-induced crescentic glomerulonephritis (CGN) using PAR-2-deficient (PAR-2(-/-)) mice and wild-type littermate controls. PAR-2(-/-) mice had reduced crescent formation, proteinuria, and serum creatinine compared with wild-type mice 21 days after initiation of CGN. Glomerular accumulation of CD4(+) T cells and macrophages and the number of proliferating cells in glomeruli were similar in both groups. Glomerular fibrin deposition was significantly reduced in PAR-2(-/-) mice, and this was associated with reduced renal plasminogen activator inhibitor expression and increased renal matrix-metalloprotinase-9 activity. These results demonstrate a proinflammatory role for PAR-2 in CGN that is independent of effects on glomerular leukocyte recruitment and mesangial cell proliferation. PAR-2-mediated augmentation of renal plasminogen activator inhibitor expression and inhibition of matrix-metalloprotinase-9 activity may contribute to increased glomerular fibrin accumulation and glomerular injury in CGN.
Moussa
Leon
L
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.
Apostolopoulos
Jim
J
Davenport
Piers
P
Tchongue
Jorge
J
Tipping
Peter G
PG
D000818:Animals; D005337:Fibrin / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism*; D058258:Serpin E2; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D044464:Receptor, PAR-2; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D005337:Fibrin; D013925:Thromboplastin; D020782:Matrix Metalloproteinases