Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways.
Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis. Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGFbeta(1), collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cell-mediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and calcineurin-dependent pathways.
Finckenberg
Piet
P
Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
Inkinen
Kaija
K
Ahonen
Juhani
J
Merasto
Saara
S
Louhelainen
Marjut
M
Vapaatalo
Heikki
H
Müller
Dominik
D
Ganten
Detlev
D
Luft
Friedrich
F
Mervaala
Eero
E
D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D019703:Calcineurin / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine / Q000378:metabolism; D000068338:Everolimus; D005786:Gene Expression Regulation; D006321:Heart / Q000033:anatomy & histology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000378:metabolism; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D007668:Kidney / Q000033:anatomy & histology / Q000473:pathology; D008297:Male; D030781:Organisms, Genetically Modified; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D024042:Collagen Type I; D024061:Collagen Type III; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine; D000068338:Everolimus; D019703:Calcineurin; D012083:Renin; D020123:Sirolimus