Des-Arg(10)-kallidin engagement of the B1 receptor stimulates type I collagen synthesis via stabilization of connective tissue growth factor mRNA

Expression of the kinin B1 receptor is up-regulated in chronic inflammatory and fibrotic disorders; however, little is known about its role in fibroge nesis. We examined human embryonic lung fibroblasts that constitutively exp ress the B1 receptor and report that engagement of the B1 receptor by des-A rg(10)-kallidin stabilized connective tissue growth factor (CTGF) mRNA, sti mulated an increase in al(I) collagen mRNA, and stimulated type I collagen production. These events were not observed in B2 receptor activated fibrobl asts. In addition, B1 receptor activation by des-Arg(10)-kallidin induced a rise in cytosolic Ca2+ that is consistent with B1 receptor pharmacology. O ur results show that the des-Arg(10)-kallidin-stimulated increase in alpha 1(I) collagen mRNA was time- and dose-dependent, with a peak response obser ved at: 20 h with 100 nM des-Arg(10)-kallidin. The increase in CTGF mRNA wa s also time- and dose-dependent, with a peak response observed at 4 h with 100 nM des-Arg(10)-kallidin. The increase in CTGF mRNA was blocked by the B 1 receptor antagonist des-Arg(10),Leu(9)-kallidin. Inhibition of protein sy nthesis by cycloheximide did not block the des-Arg(10)-kallidin-induced inc rease in CTGF mRNA. These results suggest that engagement of the kinin B1 r eceptor contributes to fibrogenesis through increased expression of CTGF.