Induction of connective tissue growth factor by angiotensin II: integration of signaling pathways.
OBJECTIVE
Angiotensin II is recognized as one of the major mediators of cardiovascular pathology. Because connective tissue growth factor (CTGF) is involved in the pathophysiologic processes underlying fibrotic diseases, its regulation by angiotensin II was investigated.


RESULTS
In the 2-kidney, 1-clip model of renovascular hypertension, increased expression of CTGF was detectable in the hypertrophic left ventricle. By activation of angiotensin II type 1 receptors, angiotensin II caused rapid expression of CTGF mRNA and protein in a human fibroblast cell line. Activation of the p42/44 mitogen-activated protein (MAP) kinase signaling pathway proved to be essential for angiotensin II-stimulated CTGF expression. Inhibition of MAP kinase activation by forskolin prevented CTGF induction. Inhibition of the isoprenylation of small GTPases by simvastatin or pretreatment of the cells with toxin B reduced basal CTGF expression below detection limits and prevented induction by angiotensin II. Specific interference with RhoA signaling by Y27632 primarily reduced basal CTGF expression. There was no significant reduction of expression of angiotensin II type 1 receptors by simvastatin. These data indicate cooperation between the Rho signaling and the angiotensin II-activated MAP kinase pathways.


CONCLUSIONS
Direct induction of CTGF by angiotensin II is indicative of a role for CTGF in angiotensin II-mediated fibrosis and might be a target of antifibrotic interventions.
Iwanciw
Dominika
D
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Germany.
Rehm
Margot
M
Porst
Markus
M
Goppelt-Struebe
Margarete
M
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D055513:Connective Tissue Growth Factor; D005355:Fibrosis / Q000503:physiopathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000187:drug effects* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D011945:Receptors, Angiotensin / Q000502:physiology; D015398:Signal Transduction; D015854:Up-Regulation; D018631:ras Proteins / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology
C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D018631:ras Proteins; D020741:rho GTP-Binding Proteins