D. Ricupero, J. Romero, D. Rishikof
Apr 28, 2000
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Journal
The Journal of Biological Chemistry
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-Arg10-kallidin stabilized connective tissue growth factor (CTGF) mRNA, stimulated an increase in α1(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-Arg10-kallidin induced a rise in cytosolic Ca2+ that is consistent with B1 receptor pharmacology. Our results show that the des-Arg10-kallidin-stimulated increase in α1(I) collagen mRNA was time- and dose-dependent, with a peak response observed at 20 h with 100 nmdes-Arg10-kallidin. The increase in CTGF mRNA was also time- and dose-dependent, with a peak response observed at 4 h with 100 nm des-Arg10-kallidin. The increase in CTGF mRNA was blocked by the B1 receptor antagonist des-Arg10,Leu9-kallidin. Inhibition of protein synthesis by cycloheximide did not block the des-Arg10-kallidin-induced increase in CTGF mRNA. These results suggest that engagement of the kinin B1 receptor contributes to fibrogenesis through increased expression of CTGF.