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

Departments of Medical Biochemistry (L.-J.M., T.-X.C., T.S., H.-W.L., R.C., J.-M.L., M.O., T.J., L.W., M.I., M.H.) and Dermatology (Y.Y., K.Y., K.H.), Ehime University Medical School, Ehime 791-0295, Japan; and Institut Cochin de Genetique Moleculaire (C.N.), Paris 75014, France

Address all correspondence and requests for reprints to: Masatsugu Horiuchi, M.D., Ph.D., Department of Medical Biochemistry, Ehime University School of Medicine, Shitsukawa, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. 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 mice to a similar degree, and the AT_1a receptor was exclusively expressed as opposed to the AT_1b receptor. In wild-type fibroblasts, Ang II increased collagen synthesis accompanied by an increase in expression of tissue inhibitor of metalloproteinase (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 IGF-I-induced collagen production and inhibited TIMP-1 expression in neonatal skin fibroblasts prepared from AT_1a knockout (KO) mice. These Ang II-mediated inhibitory effects on collagen production and TIMP-1 expression observed in AT_1a 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 (Src homology 2-containing protein-tyrosine phosphatase-1) mutant inhibited the Ang II-mediated inhibitory effect on both collagen synthesis and TIMP-1 expression in AT_1a KO fibroblasts. These results suggest that AT_1a 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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