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 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.
Ricupero
D A
DA
Pulmonary Center, Departments of Medicine and Biochemistry, Boston University School of Medicine and the Boston Veterans Affairs Medical Center, Boston, Massachusetts 02118-2394, USA. ricupero@bu.edu
Romero
J R
JR
Rishikof
D C
DC
Goldstein
R H
RH
D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis*; D055513:Connective Tissue Growth Factor; D003513:Cycloheximide / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D007609:Kallidin / Q000031:analogs & derivatives* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000196:embryology; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
C526317:CCN2 protein, human; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D003094:Collagen; D003513:Cycloheximide; D008156:Luciferases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium