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.
Highlights
Kinins are involved in the regulation of a variety of physiological and cellular functions, including smooth muscle tone, pain perception, inflammation, and cellular proliferation [1, 2]
It was proposed that TGF- stimulates fibrogenesis and proliferation in fibroblasts via a mechanism that requires de novo synthesis of a secondary factor, which has been identified as connective tissue growth factor (CTGF) [18]
We found that activation of the B1 receptor by des-Arg10-kallidin induced a dose-dependent increase in cytosolic Ca2ϩ in human lung fibroblasts (Fig. 1)
Summary
Kinins are involved in the regulation of a variety of physiological and cellular functions, including smooth muscle tone, pain perception, inflammation, and cellular proliferation [1, 2]. Activation of the B1 receptor induces cellular and physiological responses that often mimic the responses observed following activation of the B2 receptor. Both receptors activate nuclear factor B in fibroblasts [6], modulate vascular tone [7], and activate phospholipase C in mesangial cells [8]. Activation of the B2 receptor induces a variety of effects, including increased neutrophil proliferation, stimulation of macrophage spreading, release of histamine from mast cells, synthesis of platelet-activating factor and prostaglandins in endothelial cells, release of tachykinin and acetylcholine from sensory nerve endings, increased microvascular permeability, and fibroblast proliferation [2]. CCN proteins possess a secretory signal peptide and four distinct protein modules: an insulin-like growth factor-binding domain, a von Willebrand factor type C repeat, a
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