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This version published online on October 9, 2003
Endocrinology, doi:10.1210/en.2003-0673
A more recent version of this article appeared on January 1, 2004
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Submitted on May 29, 2003
Accepted on October 3, 2003

Regulation of Collagen Synthesis in Mouse Skin Fibroblasts by Distinct Angiotensin II Receptor Subtypes

LI-JUAN MIN1, TAI-XING CUI1, YOKO YAHATA1, KENSHI YAMASAKI1, TETSUYA SHIUCHI1, HONG-WEI LIU1, RUI CHEN1, JIAN-MEI LI1, MIDORI OKUMURA1, TOYOHISA JINNO1, LAN WU1, MASARU IWAI1, CLARA NAHMIAS1, KOJI HASHIMOTO1, and MASATSUGU HORIUCHI1*

1 Department of Medical Biochemistry, Ehime University Medical School, Ehime 791-0295, Japan; Department of Dermatology, Ehime University Medical School, Ehime 791-0295, Japan; CNRS UPR0415-Institut Cochin de Genetique Moleculaire, Paris, France

* To whom correspondence should be addressed. E-mail: horiuchi{at}m.ehime-u.ac.jp.

We examined the possibility of whether angiotensin (Ang) II type 1 (AT1) and type 2 (AT2) receptor stimulation differentially regulates collagen production in mouse skin fibroblasts. Both AT1 and AT2 receptors were expressed in neonatal skin fibroblasts prepared from wild-type (WT) mice to a similar degree, and the AT1a receptor was exclusively expressed as opposed to the AT1b receptor. In WT fibroblasts, Ang II increased collagen synthesis accompanied by an increase in expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), and these increases were inhibited by valsartan, an AT1 receptor blocker, but augmented by PD123319, an AT2 receptor antagonist. Ang II decreased basal and insulin-like growth factor-1-induced collagen production and inhibited TIMP-1 expression in neonatal skin fibroblasts prepared from AT1a knockout (KO) mice. These Ang II-mediated inhibitory effects on collagen production and TIMP-1 expression observed in AT1a KO fibroblasts were attenuated by the addition of PD123319 or a tyrosine phosphatase inhibitor, sodium orthovanadate, but not affected by a serine/threonine phosphatase inhibitor okadaic acid. Moreover, we demonstrated that transfection of a catalytically inactive, dominant negative SHP-1 mutant inhibited the Ang II-mediated inhibitory effect on both collagen synthesis and TIMP-1 expression in AT1a KO fibroblasts. These results suggest that AT1a receptor stimulation increases collagen production in skin fibroblasts at least in part due to the inhibition of collagen degradation via the increase in TIMP-1 expression, whereas AT2 receptor stimulation exerts inhibitory effects on TIMP-1 expression, which is mediated at least partially by the activation of SHP-1, thereby possibly inhibiting collagen production.




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