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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.

	Abstract

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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.

	Introduction

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ANGIOTENSIN (ANG) II plays a key role in the regulation of cardiovascular homeostasis and exerts various actions on target organs (1, 2). To date, two distinct Ang II receptors have been cloned and designated as type 1 (AT₁) and type 2 (AT₂) receptors. Most of the known actions of Ang II are mediated by the AT₁ receptor, such as vasoconstriction, cellular growth, and accumulation of extracellular matrix (2). Accumulating evidence suggests that AT₂ receptor stimulation counteracts AT₁ receptor activation, i.e. AT₂ receptor stimulation exerts vasodilator, antigrowth, and proapoptotic effects, suggesting that the effect of Ang II is regulated by the interaction of AT₁ and AT₂ receptor-mediated signaling in various target tissues (2, 3, 4), although the functions of the AT₂ receptor are still not fully understood.

The physiological functions as well as the underlying cellular and molecular mechanisms of the AT₁ receptor in the cardiovascular system have been extensively investigated, whereas the role of Ang II receptors in skin has not been well established despite the potential importance of Ang II in this tissue. Viswanathan and Saavedra (5) reported that the expression of Ang II receptors was significantly enhanced in the dermis as well as in a localized band within the superficial dermis of the skin surrounding a wound 3 d after wounding in the rat and that the major proportion of this increase was due to AT₂ receptors, suggesting a physiological role for AT₂ receptors in the process of tissue repair. In contrast, it has been reported that adult rat skin contains predominantly AT₁ receptors, that these receptors were down-regulated for 12–24 h after wounding and the binding recovered to baseline levels by 3 d (6), and that an immediate and transient reduction in AT₁ receptor expression occurred after wounding, followed by an increase in the number of AT₁ receptors that was maintained for 5–7 d postoperatively (7). Moreover, Ang II has been demonstrated to accelerate the closure of thermal injuries and full-thickness dermal lesions, as well as increase the survival of random flaps in rodent models, which were associated with enhancement of several physiological processes necessary for skin wound repair such as proliferation of epidermal stem cells at the base of hair follicles and production of extracellular matrix (ECM) (8, 9, 10). These results suggest that the balance of the expression of AT₁ and AT₂ receptors, as well as local production of Ang II, could influence the pathogenesis of skin wound healing.

Collagen, an extracellular macromolecule, is the most abundant structural protein in connective tissue. In skin, the fibroblast is pivotal for collagen production, and numerous collagenous structures need to be reconstituted after injury of the skin to normalize the function of this tissue. To examine the roles of Ang II in collagen production in skin fibroblasts, we focused on the roles of the AT₁ and AT₂ receptors in the regulation of collagen metabolism using cultured skin fibroblasts prepared from neonatal mice, which express both AT₁ and AT₂ receptors, and explored the signaling mechanisms involved in Ang II-regulated collagen production.

	Materials and Methods

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Cell culture and radioligand receptor binding assay
Fibroblasts were prepared from the skin of neonatal mice, as described previously with minor modifications (11), and used at passage 4 or 5. Male AT_1a receptor knockout (KO) mice (12) (donated by Tanabe Seiyaku Co. Ltd., Osaka, Japan) and wild-type (WT) mice (based on C57BL/6J strain; Clea Japan Inc., Osaka, Japan) were used in this study. The Animal Studies Committee of Ehime University approved the following experimental protocol. Briefly, skin was removed from newborn mice. The epidermis and dermis were separated by floating skin on 0.1% (wt/vol) dispase (Sanko Pure Chemical, Ltd., Tokyo, Japan) in DMEM at 4 C overnight. Fibroblasts were isolated by mincing the dermis into small pieces, followed by digestion with 0.75% collagenase (Wako Pure Chemical Industries, Ltd., Osaka, Japan) in DMEM for 1 h at 37 C. The digest was then rinsed once with DMEM and cultured in DMEM supplemented with 10% fetal bovine serum and penicillin/streptomycin (100 U/100 µg/ml) at 37 C in a humidified atmosphere of 5% CO₂ and 95% air. Expression of AT₁ and AT₂ receptors was measured by radioligand binding assay as described previously (13). Briefly, AT₁ and AT₂ receptor binding was measured using subconfluent cells grown in 24-well plates. The cells were incubated for 1 h at 37 C with 0.1 nM ¹²⁵I-labeled [Sar¹,Ile⁸] Ang II (DuPont NEN Research Products, Boston, MA) in the absence (for total count) or presence of 10 µM valsartan (Novartis Pharma AG, Basel, Switzerland) or 10 µM PD123319 (Sigma, St. Louis, MO). AT₁ receptor binding was calculated as the difference between the total count and the count from samples incubated with valsartan. AT₂ receptor binding was determined by subtracting the count of samples incubated with PD123319 from the total count.

Plasmid constructs and transfection
SHP-1 (Src homology 2-containing protein-tyrosine phosphatase-1) (C453/S) mutant cDNA, in which the active site cystein 453 was converted to serine, was inserted into the pcDNA3 vector (14), and transient transfection of the dominant negative SHP-1 (dnSHP-1, C453/S) was performed with LipofectAMINE PLUS Reagent (Invitrogen Corp., Carlsbad, CA) as described previously (13, 15).

RT-PCR
Total RNA was extracted from skin fibroblasts with TRIzol Reagent (Invitrogen Life Technologies, Gaithersburg, MD). RT-PCR was performed as described previously (16, 17). PCR primers for collagen type I were 5'-TGTTCGTGGTTCTCAGGGTAG-3' (forward) and 5'-TTGTCGTAGCAGGGTTCTTTC-3' (reverse) (18). We designed PCR primers for collagen type III as 5'-TGCCCACAGCCTTCTACACCT-3' (forward) and 5'-CCAGCTGGGCCTTTGATACCT-3' (reverse) (TaKaRa). PCR primers for tissue inhibitor of metalloproteinase (TIMP)-1 were 5'-AGACCACCTTATACCAGCGT-3' (forward) and 5'-TAAACAGGGAAACACTGTGC-3' (reverse) (19, 20). PCR amplifications were carried out with 30 cycles for collagen type I, AT₁, AT_1a, AT_1b, and AT₂ receptors, and TIMP-1, and with 25 cycles for collagen type III and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). To verify the identity of the PCR products, we sequenced PCR products and confirmed that the sequences of PCR products matched the predicted sequences. PCR-amplified DNAs of TIMP-1 and GAPDH were subcloned into pGEM-T Easy Vector (Promega Corp., Madison, WI), and cDNA probes for Northern blotting were prepared from this plasmid vector.

Determination of collagen production
Collagen production was determined by measuring [³H]proline incorporation into collagenous proteins as described previously with minor modulations (21). Confluent skin fibroblasts cultured in 24-well plates were maintained in DMEM supplemented with 0.1% fetal bovine serum for 48 h and then treated for 36 h with Ang II, valsartan, PD123319, and/or IGF-I and pulsed with 4 µCi/ml [³H]proline (DuPont NEN Research Products) during the last 24 h. Two separate 200-µl aliquots of conditioned medium were mixed with 3 mM CaCl₂, 1 mM phenylmethylsulfonylfluoride, 5 mM N-ethylmaleimide, and 25 µg BSA with 100 U/ml collagenase or vehicle (PBS), and then incubated for an additional 4 h at 37 C. The proteins were precipitated with 10% trichloroacetic acid for 30 min at 4 C. After centrifugation, pellets were washed with 10% trichloroacetic acid and solubilized in 0.3 N NaOH/1% sodium dodecyl sulfate for liquid scintillation counting. Radioactivity in protein pellets from PBS- and collagenase-treated culture medium represents total and noncollagenous protein (collagenase-resistant [³H]proline uptake), respectively. [³H]proline uptake into collagenous protein (collagenase-sensitive [³H]proline, collagen production) was calculated by subtracting the collagenase-resistant uptake from the total uptake.

Western blot analysis
Total protein were obtained from neonatal skin fibroblast lysates prepared from both WT and AT_1a KO mice without stimuli and/or with Ang II, valsartan, PD123319 and then separated by standard SDS-PAGE and transferred to a nitrocellulose membrane (Amersham Biosciences, Piscataway, NJ). Western blot analysis was performed using standard techniques and appropriate anti-SHP-1 antibody, anti-TIMP-1 antibody (CHEMICON International, Inc., Temecula, CA). Enhanced chemiluminescence (Amersham) was used for the detection.

Northern blot analysis
After size-fractionation on a denaturing agarose-formaldehyde gel, total RNA (25 µg) was transferred to a nylon membrane (Hybond-N+, Amersham Pharmacia Biotech, Uppsala, Sweden). Hybridization was carried out with ³²P-labeled probes of TIMP-1 and GAPDH. Densitometric analysis was performed using an image scanner (EPSON GT-8000; Epson, Tokyo, Japan) and National Institutes of Health (Bethesda, MD) imaging software.

Statistical analysis
All values are expressed as mean ± SEM. The data were evaluated by ANOVA followed by post hoc analysis for multiple comparisons. The difference was considered to be significant if P < 0.05.

	Results

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Ang II receptors in cultured neonatal mouse skin fibroblasts
Radioligand receptor binding assay showed that skin fibroblasts (passage 4 or 5) prepared from WT mice skin expressed AT₁ and AT₂ receptors (mean ± SEM, 0.75 ± 0.09 and 0.94 ± 0.09 fmol/10⁶ cells, respectively; n = 4) and that skin fibroblasts prepared from AT_1a KO mice skin expressed the AT₂ receptor (mean ± SEM, 0.81 ± 0.10 fmol/10⁶ cells; n = 4) without detectable level of AT₁ receptor (Fig. 1A). Consistent with these results, RT-PCR demonstrated that the expression of AT₂ receptor mRNA was comparable between WT and AT_1a KO mice (Fig. 1B). Moreover, the expression of AT_1b receptor mRNA was similar in both strains, although this receptor expression was low compared with that of the AT_1a receptor. We observed that expression of the AT₂ receptor appeared to be increased, whereas that of the AT₁ receptor decreased after passage 6 in neonatal skin fibroblasts under our experimental conditions (data not shown). Therefore, the following experiments were performed using cells at passage 4 or 5.

View larger version (30K): [in this window] [in a new window]   FIG. 1. Expression of AT1 and AT2 receptors in cultured neonatal skin fibroblasts prepared from WT and AT1aKO mice. A, Radioligand binding assay was performed as described in Materials and Methods. Values are expressed as mean ± SEM (n = 4). Similar results were obtained in three different culture lines. B, RT-PCR showing the mRNA expression of AT1a receptor, AT1b receptor, and AT2 receptor. The results show the representative data of three separate experiments. GAPDH was used as an internal control to standardize the amount of total RNA used.

View larger version (47K): [in this window] [in a new window]   FIG. 2. Effect of Ang II- and/or IGF-I on collagen synthesis in neonatal skin fibroblasts (A and C). Quiescent confluent skin fibroblasts prepared from WT and AT1a KO mice were incubated with Ang II (100 nM) (A) and/or IGF-1 (100 ng/ml) (C) with or without valsartan (10 µM), an AT1 receptor specific blocker, and PD123319 (10 µM), an AT2 receptor antagonist, for 36 h and subjected to collagen synthesis assay as described in Materials and Methods. Open columns show total [3H]proline incorporation, and hatched columns show [3H]proline incorporation resistant to collagenase digestion. Values are expressed as mean ± SEM (n = 4). Similar results were obtained in three different cultured cell lines. *, P < 0.05 vs. control. B, Effect of Ang II on collagen type I and type III mRNA expression in skin fibroblasts by RT-PCR. Collagen mRNA expression by Ang II (100 nM) stimulation with or without valsartan (10 µM) and PD123319 (10 µM) for 6 h in skin fibroblasts prepared from WT and AT1a KO mice is also shown. The results show the representative data of three separate experiments. GAPDH was used as an internal control to standardize the amount of total RNA used.

View larger version (49K): [in this window] [in a new window]   FIG. 3. Effects of Ang II receptor stimulation on IGF-I- or basic fibroblast growth factor (bFGF)-mediated collagen mRNA expression in neonatal skin fibroblasts prepared from WT and AT1a KO mice by RT-PCR. Total RNA was extracted from both skin fibroblasts treated with IGF-I (100 ng/ml) (A) or bFGF (10 ng/ml) (B), and/or Ang II (100 nM) with or without valsartan (10 µM) and PD123319 (10 µM). RT-PCR was performed as described in Materials and Methods. The results show the representative data of three separate experiments. GAPDH was used as an internal control to standardize the amount of total RNA used.

View larger version (35K): [in this window] [in a new window]   FIG. 4. Effect of sodium orthovanadate (Na3VO4) or okadaic acid on Ang II-induced inhibition of collagen synthesis in neonatal skin fibroblasts prepared from AT1a KO mice. Quiescent confluent cells pretreated with vehicle (A), sodium orthovanadate (0.1 µM) (B), or okadaic acid (0.1 µM) (C) for 16 h were incubated with Ang II (100 nM) and/or IGF-I (100 ng/ml) in the presence or absence of PD123319 (10 µM) for 36 h. Collagen synthesis was determined as described in Materials and Methods. Open columns show total [3H]proline incorporation, and hatched columns show [3H]proline incorporation resistant to collagenase digestion. Values are expressed as mean ± SEM (n = 4). Similar results were obtained in three different cultured cell lines. *, P < 0.05 vs. control.

View larger version (35K): [in this window] [in a new window]   FIG. 5. Role of SHP-1 in inhibitory effect of Ang II on collagen synthesis in neonatal skin fibroblasts prepared from AT1a KO mice. Quiescent confluent cells transfected with control vector pcDNA3 (A) or dnSHP-1 (B) were treated with Ang II (100 nM) and/or IGF-I (100 ng/ml) with or without PD123319 (10 µM) for 36 h. Collagen synthesis was determined as described in Materials and Methods. Open columns show total [3H]proline incorporation, and hatched columns show [3H]proline incorporation resistant to collagenase digestion. Values are expressed as mean ± SEM (n = 4). Similar results were obtained in three different cultured cell lines. *, P < 0.05 vs. control. C, Protein level of SHP-1 in neonatal skin fibroblasts prepared from both WT and AT1a KO mice was detected by Western blot analysis. The result show the representative data of three separate experiments.

View larger version (31K): [in this window] [in a new window]   FIG. 6. Effect of Ang II on TIMP-1 mRNA expression in neonatal skin fibroblasts (A, B). Quiescent confluent skin fibroblasts prepared from WT (A) and AT1a KO (B) mice were stimulated by the addition of Ang II (100 nM) for the indicated times (left panels). Cells prepared from WT (A) and AT1a KO (B) mice were incubated with Ang II (100 nM) with or without valsartan (10 µM) and PD123319 (10 µM) for 6 h (right panels). TIMP-1 mRNA expression was determined by Northern blot analysis as described in Materials and Methods. Values are expressed as mean ± SEM (n = 4). The results (upper panels) show representative data of four separate experiments. *, P < 0.05 vs. control. C, Effect of Ang II on TIMP-1 protein expression in skin fibroblasts by Western blot analysis. Quiescent confluent skin fibroblasts were stimulated by the addition of Ang II (100 nM) for the indicated times. Western blot analysis was performed as described in Materials and Methods. The results show the representative data of three separate experiments.

View larger version (34K): [in this window] [in a new window]   FIG. 7. Role of SHP-1 in inhibitory effect of Ang II on TIMP-1 mRNA expression in neonatal skin fibroblasts of AT1a KO mice. Quiescent confluent cells transfected with control vector pcDNA3 or dnSHP-1 were treated with Ang II (100 nM) with or without PD123319 (10 µM) for 6 h. TIMP-1 mRNA expression was determined by Northern blot analysis as described in Materials and Methods. Values are expressed as mean ± SEM (n = 4). The results (upper panels) show representative data of four separate experiments. *, P < 0.05 vs. control.

	Discussion

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The timely breakdown of ECM is essential for embryonic development, morphogenesis, reproduction, and tissue resorption and remodeling, and the matrix metalloproteinases (MMPs) are thought to play a central role in these processes (28). The proteolytic activities of MMPs are precisely controlled during activation from their precursors and inhibition by endogenous inhibitors, -macroglobulins and TIMPs. TIMPs are the major endogenous regulators of MMP activities in tissue, and four homologous TIMPs have been identified and characterized to date, designated as TIMP-1, TIMP-2, TIMP-3, and TIMP-4 (29). There is evidence that TIMP-1 has important roles in skin wound healing (19, 30, 31). We demonstrated that AT₁ receptor stimulation increased TIMP-1 expression; however, AT₂ receptor stimulation inhibited TIMP-1 expression in mouse neonatal skin 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, resulting in an increase in collagen degradation and thereby apparent inhibition of collagen production. In accordance with our observation, Chua et al. (32) have reported that Ang II induces TIMP-1 production in rat endothelial cells.

Although both the AT₁ and AT₂ receptors belong to the seven-transmembrane, G protein-coupled receptor family and share approximately 30% primary sequence homology, recent evidence has revealed that the functions of the AT₁ and AT₂ receptors are mutually antagonistic in various cells and tissues (2, 3). Moreover, based on the restricted expression of the AT₂ receptor in fetal tissues as well as in disease states, such as myocardial infarction and vascular injury, this receptor is thought to be involved in growth, development, and/or differentiation. The AT₂ receptor displays totally different signaling mechanisms from the AT₁ receptor. Indeed, AT₂ receptor stimulation leads to the activation of various phosphatases, whereas the AT₁ receptor activates a set of protein tyrosine kinases, which are involved in the induction of immediate early genes (33, 34). The overall cellular effect of AT₂ and AT₁ receptors costimulation is a premature termination of AT₁ receptor-elicited cell growth signals by the AT₂ receptor. The signaling mechanism of the AT₂ receptor has not been well defined compared with that of the AT₁ receptor. The growth inhibitory effects of the AT₂ receptor are reported to be at least partly mediated by activation of a variety of phosphatases, which results in the inactivation of AT₁ receptor- and/or growth factor-activated ERK. It has been shown that AT₂ receptor stimulation leads to activation of a series of phosphatases, including the protein tyrosine phosphatase SHP-1, mitogen-activated protein kinase phosphatase-1, and the serine/threonine phosphatase 2A, which results in inactivation of AT₁ receptor- and/or growth factor-activated growth-promoting signaling (2, 3). SHP-1 tyrosine phosphatase has been suggested to be an early transducer of the AT₂ receptor signaling pathway involved in functional negative cross-talk between heptahelical AT₂ receptors and receptor tyrosine kinases (14). In this study, we observed that transfection of dnSHP-1 significantly restored the AT₂ receptor-mediated inhibition of TIMP-1 expression and collagen production in fibroblasts prepared from AT_1a KO mice, whereas the addition of okadaic acid did not affect Ang II-mediated collagen production, which suggests that SHP-1 is pivotal in AT₂ receptor-regulated collagen metabolism. It is not clear whether SHP-1 directly regulates TIMP-1 expression and collagen metabolism, and it is possible that Ang II may target the factors downstream of SHP-1 cascade. Detailed investigation will provide more information to understand further mechanisms of collagen metabolism, because SHP-1 physically interacts with a number of membrane receptors, such as nerve growth factor Trk receptor, epidermal growth factor receptor, c-kit (stem cell factor) receptor, IL-3 receptor, erythropoietin receptor, and B cell FcRIIB receptor, an allotype of Fc receptor (35, 36, 37, 38, 39, 40), to terminate their signal. We also reported that SHP-1 is also important in estrogen and TNF- signaling cascade (41, 42).

Our finding in this study of coordination of collagen production by the antagonistic actions of the AT_1a and AT₂ receptors in skin fibroblasts provides new insights into the pathophysiological significance of Ang II in the skin. Detailed analysis of the specific cell type expressing AT₁ and AT₂ receptors and their localization in the process of skin wound healing as well as other Ang II-regulated cellular responses, such as cell proliferation, inflammation, and oxidative stress, will provide more pathophysiological significance of Ang II in this tissue.

	Footnotes

 
This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan, the Japan Research Foundation for Clinical Pharmacology, the Tokyo Biochemical Research Foundation, and the Smoking Research Foundation.

L.-J.M. and T.-X.C. contributed equally to this work.

Abbreviations: Ang, Angiotensin; AT₁, angiotensin II type 1; AT₂, angiotensin II type 2; dnSHP-1, dominant negative SHP-1; ECM, extracellular matrix; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; KO, knockout; MMP, matrix metalloproteinase; SHP-1, Src homology 2-containing protein-tyrosine phosphatase-1; TIMP, tissue inhibitor of metalloproteinase; WT, wild-type.

Received May 29, 2003.

Accepted for publication October 3, 2003.

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