Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis.
BACKGROUND
Angiotensin II (Ang II) participates in the development of fibrosis during vascular damage. Connective tissue growth factor (CTGF) is a novel fibrotic mediator. However, the potential link between CTGF and Ang II has not been investigated.


RESULTS
In vivo Ang II effects were studied by systemic infusion into normal rats to evaluate CTGF and extracellular matrix protein (ECM) expression by immunohistochemistry. In aorta of Ang II-infused rats, CTGF staining was markedly increased and ECM overexpression was observed. An AT1 antagonist diminished CTGF and ECM. In growth-arrested vascular smooth muscle cells, Ang II induced CTGF mRNA expression after 1 hour, remained elevated up to 24 hours, and increased CTGF protein production, which was increased up to 72 hours. The AT1 antagonist blocked Ang II-induced CTGF gene and protein expression. Early CTGF upregulation is independent of new protein synthesis. Several intracellular signals elicited by Ang II are involved in CTGF synthesis, including protein kinase C activation, reactive oxygen species, and transforming growth factor-beta endogenous production. Incubation with a CTGF antisense oligonucleotide decreased CTGF and fibronectin upregulation caused by Ang II.


CONCLUSIONS
Our results show that Ang II, via AT1, increases CTGF in vascular cells both in vivo and in vitro. This novel finding suggests that CTGF may be a mediator of the profibrogenic effects of Ang II in vascular diseases.
Rupérez
Mónica
M
Vascular and Renal Research Laboratory, Autónoma University, Fundación Jiménez Díaz, Avda Reyes Católicos, 2, 28040 Madrid, Spain.
Lorenzo
Oscar
O
Blanco-Colio
Luis Miguel
LM
Esteban
Vanesa
V
Egido
Jesús
J
Ruiz-Ortega
Marta
M
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2
D057911:Angiotensin Receptor Antagonists; C526316:CCN2 protein, rat; D016326:Extracellular Matrix Proteins; D007093:Imidazoles; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; C073402:PD 123319; D055513:Connective Tissue Growth Factor; D019808:Losartan