PAR-2 deficiency is protective in crescentic experimental GN
Protease activated receptor 2 (PAR-2) is a cellular receptor strongly expressed on renal epithelial, mesangial and endothelial cells as well as on macrophages. PAR-2 activation follows N-terminal cleavage by serine proteases such as trypsin, tryptase, and coagulation factors VIIa and Xa. This results in pleiotropic effects including vasodilatation, elevated plasminogen activator inhibitor (PAI-1) expression by endothelial cells and cytokine release from macrophages. The role of PAR-2 in renal inflammation was studied in anti-glomerular basement membrane antibody induced crescentic glomerulonephritis (CGN) using PAR-2 deficient mice (PAR-2 KO) and wild type littermate controls (WT). PAR-2 KO mice had reduced crescent formation (% glomeruli affected: PAR-2 KO, 8.9 ± 2.4; WT 24.5 ± 4.9; p = 0.01), less proteinuria (mg/24h: PAR-2 KO, 2.1 ± 0.7; WT, 11.5 ± 2.9; p = 0.006) and lower serum creatinine (μmol/L: PAR-2 KO, 25.7 ± 1.3; WT, 36.3 ± 3.2; p = 0.01). Glomerular accumulation of CD4+ T cells and macrophages were similar in both groups. However, glomerular fibrin deposition was significantly reduced in PAR-2 KO mice (fibrin score: PAR-2 KO, 0.93 ± 0.08; WT, 1.22 ± 0.07; p = 0.02). These results demonstrate a pro-inflammatory role for PAR-2 in CGN, which appears to be independent of leukocyte recruitment into glomeruli. Fibrin is an important mediator of injury in this model and augmentation of glomerular fibrin deposition by induction of PAI-1 expression may contribute to injurious role of PAR-2.