Pharmacological inhibition of protease‐activated receptor‐2 reduces crescent formation in rat nephrotoxic serum nephritis

Abstract

Summary Glomerular crescent formation is a hallmark of rapidly progressive forms of glomerulonephritis. Thrombosis and macrophage infiltration are features of crescent formation in human and experimental kidney disease. Protease‐activated receptor‐2 (PAR‐2) is a G‐protein coupled receptor that links coagulation and inflammation. This study investigated whether pharmacological inhibition of PAR‐2 can suppress glomerular crescent formation in rat nephrotoxic serum nephritis (NTN). Disease was induced in Wistar Kyoto rats by immunisation with sheep IgG followed by administration of sheep nephrotoxic serum. Rats (n = 8/group) received the PAR‐2 antagonist (GB88, 10 mg/kg/p.o.), vehicle or no treatment starting 3 days before nephrotoxic serum injection and continuing until day 14. Vehicle and untreated rats developed thrombosis and macrophage infiltration in the glomerular tuft and Bowman's space in conjunction with prominent crescent formation. Activation of JNK signalling and proliferation in parietal epithelial cells was associated with crescent formation. GB88 treatment significantly reduced crescent formation with a substantial reduction in glomerular thrombosis, reduced macrophage infiltration in Bowman's space, and reduced activation of parietal epithelial cells. However, GB88 did not protect against the development of proteinuria, renal function impairment, inflammation or tubular cell damage in the NTN model. In conclusion, PAR‐2 plays a specific role in glomerular crescent formation by promoting glomerular thrombosis, macrophage accumulation in Bowman's space and activation of parietal epithelial cells.

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

“…In a rat model of crescentic glomerulonephritis, administration of a PAR2 antagonist (GB88) reduced glomerular thrombosis and crescent formation; however, GB88 failed to protect against upregulation of Ccl2 or Tnf mRNA levels, interstitial macrophage infiltration or tubular damagealthough little thrombosis was evident in the tubulointerstitial compartment. 26 Administration of a different PAR2 antagonist (FSLLRY-NH2) suppressed glomerular damage and renal impairment in rat model of adriamycin nephropathy, although tubulointerstitial damage was not assessed. 27 On the other hand, Par2−/− mice show a modest, but significant, protection from adenine-induced tubulointerstitial injury.…”

Expression of protease activated receptor-2 is reduced in renal cell carcinoma biopsies and cell lines

“…These reports of enhanced expression of PAR2 in cancer pathogenesis have led to it being promoted as a drug target worthy of investigation [26,27]. Potent, selective and bioavailable PAR2 antagonists have shown therapeutic efficacy in animal models of inflammatory bowel disease (IBD), arthritis and glomerulonephritis [18,34,35,38]. This has raised the possibility that PAR2 antagonists might be useful in the treatment of cancers where PAR2 is overexpressed.…”

“…Thus, we were encouraged to investigate whether increased PAR2 expression could enhance RCC growth and progression. If so, we planned to use highly potent and bioavailable PAR2 antagonists [33][34][35] to test the functional role of increased PAR2 expression in RCC cell lines and in a mouse xenograft model. In the present study, we examined PAR2 expression in our a bank of human kidney cancer tissues and cell lines as a forerunner to evaluating therapeutic effects of PAR2 antagonists.…”

PAR2-Induced Tissue Factor Synthesis by Primary Cultures of Human Kidney Tubular Epithelial Cells Is Modified by Glucose Availability

“…In a model of crescentic glomerulonephritis deposition of fibrin and expression of plasminogen activator inhibitor are reduced in PAR-2 −/− mice [ 36 ]. Further to this pharmacologically blocking PAR2 also reduce glomerular crescent formation and glomerular fibrin deposition [ 23 ]. A role for PAR2 in diabetic kidney disease has also been reported [ 37 ].…”

“…In addition to proteases, synthetic peptides of six amino acids, such as 2-furoyl-LIGRLO-NH 2 (2F), have been widely used as exogenous agonists to investigate roles for PAR2 in physiological and pathophysiological situations. Within the human kidney, PAR2 is especially prominent in the tubule epithelial cells of the kidney cortex and kidney vasculature and enhanced expression in these cells has been reported in various inflammatory kidney diseases [ 20 , 22 , 23 ].…”