Des-Arg10-kallidin Engagement of the B1 Receptor Stimulates Type I Collagen Synthesis via Stabilization of Connective Tissue Growth Factor mRNA

Abstract

Expression of the kinin B1 receptor is up-regulated in chronic inflammatory and fibrotic disorders; however, little is known about its role in fibrogenesis. We examined human embryonic lung fibroblasts that constitutively express the B1 receptor and report that engagement of the B1 receptor by des-Arg(10)-kallidin stabilized connective tissue growth factor (CTGF) mRNA, stimulated an increase in alpha1(I) collagen mRNA, and stimulated type I collagen production. These events were not observed in B2 receptor-activated fibroblasts. In addition, B1 receptor activation by des-Arg(10)-kallidin induced a rise in cytosolic Ca(2+) that is consistent with B1 receptor pharmacology. Our results show that the des-Arg(10)-kallidin-stimulated increase in alpha1(I) collagen mRNA was time- and dose-dependent, with a peak response observed at 20 h with 100 nM des-Arg(10)-kallidin. The increase in CTGF mRNA was 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 B1 receptor antagonist des-Arg(10),Leu(9)-kallidin. Inhibition of protein synthesis by cycloheximide did not block the des-Arg(10)-kallidin-induced increase in CTGF mRNA. These results suggest that engagement of the kinin B1 receptor contributes to fibrogenesis through increased expression of CTGF.