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(Hypertension. 1995;26:665-669.)
© 1995 American Heart Association, Inc.

Articles

Glucocorticoids Regulate V_1a Vasopressin Receptor Expression by Increasing mRNA Stability in Vascular Smooth Muscle Cells

Satoshi Murasawa; Hiroaki Matsubara; Kazuhisa Kizima; Katsuya Maruyama; Yasukiyo Mori; Mitsuo Inada

From the Second Department of Internal Medicine, Kansai Medical University, Osaka, Japan.

Correspondence to Hiroaki Matsubara, MD, PhD, Second Department of Internal Medicine, Kansai Medical University, Fumizonocho 1, Moriguchi, Osaka 570, Japan.

	Abstract

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Abstract Enhancement of vascular responsiveness is considered to be one of the major contributing factors observed in glucocorticoid-induced hypertension. We examined the effects of glucocorticoids on V_1a arginine vasopressin receptor mRNA and protein levels in vascular smooth muscle cells. Dexamethasone (1 µmol/L) produced a 1.8-fold increase in V_1a receptor density without changing its affinity. Steady-state values of V_1a receptor mRNA, analyzed by Northern blotting, increased 2.7-fold after a 12-hour exposure to dexamethasone. This effect of dexamethasone was blocked by the glucocorticoid antagonist RU38486 and did not occur in the presence of the protein synthesis inhibitor cycloheximide. The V_1a receptor gene transcription rate, determined by nuclear run-off assays, was unchanged in cells treated with dexamethasone for 12 hours. Dexamethasone increased the half-life of V_1a receptor mRNA by 2.2-fold. These findings suggest that dexamethasone upregulates the expression of the V_1a receptor by increasing mRNA stability rather than by gene transcription and that de novo protein synthesis is involved in this regulation.

Key Words: RNA, messenger • receptors, vasopressin • gene expression • glucocorticoids

	Introduction

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Glucocorticoid hormones are known to be involved in blood pressure regulation and to induce hypertension.^{1 2} Although the exact mechanisms of glucocorticoid-induced hypertension are still uncertain, enhancement of vascular responsiveness has been considered a major contributing factor.^{3 4} In fact, the expression of _1ß-adrenergic⁵ and angiotensin II⁶ receptors is increased by glucocorticoids in vascular smooth muscle cells, which may cause the vascular hyperreactivity to catecholamines and angiotensin II in patients with Cushing's syndrome⁷ and in experimental animals.⁸ Arginine vasopressin (AVP) receptors are expressed in vascular smooth muscle cells and play an important physiological role in vasoconstriction.^{9 10} Although previous studies have demonstrated the contribution of AVP to the hypertension process in several forms of hypertension, particularly in deoxycorticosterone acetate–salt hypertension¹¹ and in spontaneously hypertensive rats and stroke-prone spontaneously hypertensive rats,^{12 13} the involvement of AVP in glucocorticoid-induced hypertension remains unknown.

AVP has diverse actions, including the contraction of smooth muscle, stimulation of liver glycogenolysis, modulation of corticotropin release from the pituitary, and inhibition of diuresis.¹⁴ These physiological effects are mediated through the binding of AVP to specific membrane receptors of the target cells. AVP receptors are G protein-coupled and have been divided into at least three types (V_1a, V_1b, and V₂). The V_1a (vascular/hepatic) and V_1b (anterior pituitary) receptors act through phosphatidylinositol hydrolysis to mobilize intracellular Ca²⁺.¹⁵ The V_1a receptor mediates physiological effects such as cell contraction and proliferation, platelet aggregation, coagulation factor release, and glycogenolysis. The V_1b receptor exists in the anterior pituitary to stimulate corticotropin release. The V₂ receptors are found mainly in the kidney, are linked to adenylate cyclase and the production of cAMP, and are associated with antidiuresis.¹⁶ All of these receptors have been cloned recently^{17 18 19} and belong to the family of "seven membrane spanning" receptors, which signal through G proteins.

A previous study demonstrated that adrenalectomy reduced the AVP-sensitive adenylate cyclase activity in rat kidneys and that injection of aldosterone into adrenalectomized rats partially restored this response.²⁰ Similarly, dexamethasone has also been shown to increase AVP-sensitive adenylate cyclase in epithelial cells derived from the kidney of Xenopus laevis.²¹ Colson et al²² have shown that glucocorticoids upregulate the rat V_1a receptor number in a rat mammary tumor cell line. Although these findings suggest that glucocorticoids regulate AVP receptor expression, the molecular mechanisms responsible for the regulation have not been clarified. In the present study we report that dexamethasone upregulates V_1a receptor expression by increasing mRNA stability and that de novo protein synthesis is involved in this regulation.

	Methods

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Cell Culture
Rat aortic smooth muscle (A10) cells (Dainippon Pharmaceutical) were grown in Dulbecco's modified Eagle's medium containing 10% fetal calf serum, 100 U/mL penicillin G, and 100 µg/mL streptomycin.²³ All experiments were performed with cells passaged once a week for no more than 4 months. The cells were dissociated with 0.25% trypsin containing 0.25% EDTA (pH 7.5) and seeded in plates (35-mm diameter for binding assay and 100-mm diameter for RNA isolation). Experiments were performed after 3 to 4 days unless indicated otherwise. Dexamethasone and RU38486 (glucocorticoid antagonist, Roussel Uclaf) were resolved with ethanol and added to serum-free Dulbecco's modified Eagle's medium.

[³H]AVP Binding to Cells in Monolayer
A10 cells were washed with ice-cold binding buffer (Dulbecco's phosphate-buffered saline with 10 mmol/L MgCl₂, 0.7 mmol/L CaCl₂, 0.1% glucose, and 0.2% bovine serum albumin), and binding was initiated with 1 mL binding buffer containing 0.5 to 55 nmol/L [³H]AVP (curies per millimole, New England Nuclear) with or without 10 µmol/L AVP for 90 minutes at 4°C, as described by Stassen et al.⁹ Binding was terminated by aspirating the solution, and the unbound radioligand was removed by washing twice with ice-cold binding buffer. Bound radioactivity was removed by adding 1 mL of 0.2% sodium dodecyl sulfate (SDS)/0.2 mol/L NaOH for 5 minutes and washing with an additional 0.5 mL SDS/NaOH. Radioactivity was measured with a gamma counter (LKB Produkter). Counts were corrected for background radioactivity, and specific binding was determined by subtracting the radioactivity bound in the presence of 10 µmol/L unlabeled AVP. B_max and K_d values were calculated from Scatchard plots.^{24 25}

Northern Blotting
Total cellular RNA, isolated by the CsCl centrifugation method, was denatured with 6% formaldehyde, fractionated by 1% agarose gel electrophoresis, transferred to a nylon filter, and hybridized at 42°C for 12 to 16 hours to the V_1a receptor cDNA probe labeled with [³²P]dCTP.^{23 26} The used probe was the cDNA fragment corresponding to nucleotides -91 to +1343 of a V_1a receptor cDNA clone¹⁷ relative to the ATG initiation codon. The cDNA fragment was obtained by reverse transcriptase and polymerase chain reaction as follows. Adult rat liver total RNA (1 µg) was transcribed with random hexamers (2.5 µmol/L), dNTPs (1 mmol/L), and RNase inhibitors (1 U/µL) with the use of Moloney Murine Leukemia Virus reverse transcriptase (2.5 U/µL) for 45 minutes at 42°C as previously reported.^{24 27} The resultant single-strand cDNA was amplified with the forward primer in the 5'-noncoding region (5'-GCGCAGAGCTTAGAACTCGGATCCTCCGGT-3') and reverse primer in the 3'-noncoding region (5'-CTTTGGACGCAGTCTTGCAGGAGATGGCC-3') with the use of Taq polymerase (Takara Shuzo). The resultant polymerase chain reaction product was radiolabeled by random oligonucleotide primer extension with the use of [-³²P]dCTP and was used as a probe.²³ After hybridization the filter was washed in 0.1x SSC plus 0.1% SDS at 65°C and exposed to Kodak XAR-5 film with an intensifying screen. The used filters were boiled in 0.01x SSC plus 0.01% SDS and rehybridized to the ß-actin cDNA probe. The washing and exposure to the film were performed in the same way as that for the V_1a receptor cDNA probe.

Transcript Stability Analysis
The stability of V_1a receptor mRNA in dexamethasone-treated and control cells was measured by incubation with actinomycin D (5 µg/mL) to block transcription.^{24 28} After various incubation times, total RNA was isolated from individual dishes, and the disappearance of mRNA abundance was determined by Northern blots as mentioned above.

Nuclear Run-off Assay
The preparation of nuclei and run-off assays were performed as described previously.^{24 28} Nuclei were incubated for 20 minutes at 30°C in the presence of 50 mmol/L Tris-Cl (pH 7.9); 100 mmol/L KCl; 12.5% glycerol; 6 mmol/L MgCl_2; 0.2 mmol/L EDTA; 0.5 mmol/L dithiothreitol; 4 mmol/L each ATP, GTP, and CTP; 1 U/µL RNAsin; and 200 µCi [-³²P]UTP. After RNase-free DNase I and proteinase K digestion, the reaction products were extracted with guanidinium isothiocyanate (4 mol/L) and phenol/chloroform, and unincorporated [-³²P]UTP was removed by trichloroacetic acid precipitation and filtration. The radiolabeled RNA (3x10⁶ cpm) was hybridized at 42°C for 48 hours with linearized pBluescript II KS(-) plasmids containing rat V_1a receptor cDNA (15 µg), rat angiotensin II type 1 receptor cDNA (15 µg), or ß-actin cDNA fragments (5 µg). The membrane was washed in 2x SSC plus 0.1% SDS at room temperature for 5 minutes three times and 0.2x SSC plus 0.1% SDS at 65°C for 15 minutes twice, and then the bound radioactivity was determined by scintillation counting.

Reagents and Statistical Methods
All reagents were purchased from Sigma Chemical Co unless otherwise indicated. Results are expressed as mean±SEM. ANOVA and Fisher's protected least significant difference test were used for multigroup comparisons. Values of P<.05 were considered statistically significant.

	Results

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Effect of Glucocorticoids on Rat V_1a Receptor Protein and mRNA Levels
Colson et al²² reported that rat V_1a receptor protein is upregulated by glucocorticoids in rat mammary tumor cells. We examined the effect of glucocorticoids on V_1a receptor expression in rat vascular smooth muscle (A10) cells expressing the V_1a receptor at a high density.¹⁰ To examine the effect of glucocorticoids on V_1a receptor protein, we incubated A10 cells with dexamethasone (1 µmol/L). AVP binding to cells in monolayer was performed as previously described for A10 cells by Stassen et al.⁹ At 4°C specific binding reached a plateau after 60 minutes at 0.5 to 55 nmol/L [³H]AVP, and Scatchard analysis of these data indicated the presence of a single high-affinity binding site (8.4±0.1 nmol/L, n=5) similar to that (8.1 nmol/L) reported by Stassen et al.⁹ As shown in Fig 1A, V_1a receptor density was significantly increased (1.8-fold, n=5) after a 6-hour exposure to dexamethasone and reached a maximal level at 12 hours (3.2-fold, n=5). The B_max value was initially 86±3 fmol per 10⁶ cells (n=5), and dexamethasone did not significantly change the K_d value of a single binding site for the ligand (8.3±0.1 nmol/L, n=5).

View larger version (51K): [in this window] [in a new window]   Figure 1. Bar graphs and blots show receptor binding and Northern blot analyses of dexamethasone-induced changes of rat V1a receptor density and mRNA in A10 cells. A, A10 cells were exposed to dexamethasone (DEX, 1 µmol/L) for 6 to 24 hours. V1a Bmax was measured by Scatchard plots. Data are mean±SEM of five separate experiments. B, mRNA abundance (20 µg) was determined by Northern blotting with the use of rat V1a cDNA and ß-actin cDNA probes. Autoradiograms were scanned by a densitometer. A10 cells were pretreated with RU38486 (RU, 10 µmol/L) for 30 minutes or cycloheximide (CX, 5 µg/mL) for 2 hours and then exposed to dexamethasone (1 µmol/L) for 12 hours. C, V1a receptor mRNA (2.8 kb) levels are expressed relative to ß-actin mRNA on the same filter. Results are mean±SEM of three separate experiments. *P<.01 vs control values. CTL indicates control.

The steady-state V_1a receptor mRNA level was measured by Northern blot analyses. Three sizes of mRNA signals were observed in A10 cells (2.8, 2.1, and 1.9 kb), and they showed the same relative proportions throughout the experiments involving dexamethasone treatment (Fig 1B and 1C). These signals were positive even after the filters were washed at high stringency in 0.1x SSC at 65°C. Morel et al¹⁷ showed that a single signal of 2.1-kb mRNA was exclusively expressed in rat liver, kidneys, spleen, and testis; they did not study the expression profile in vascular smooth muscle cells such as A10 cells. As shown in Fig 1B, the addition of dexamethasone induced a significant increase in each of the three different sizes of the V_1a receptor mRNA. The maximal accumulation was found at 12 hours; this gradually declined over the next few hours. Throughout the experimental period the abundance of ß-actin mRNA did not change (Fig 1B); therefore, we used ß-actin mRNA as an internal control for minor fluctuations in mRNA applied to the gel. Fig 1C illustrates the relative increase in the ratio of V_1a receptor mRNA and ß-actin mRNA. The maximal increases in the 2.8-, 2.1-, and 1.9-kb V_1a receptor mRNAs were 2.7-fold, 3.1-fold, and 2.8-fold, respectively, at 12 hours (data for 2.8-kb mRNA are shown in Fig 1C). RU38486, a specific glucocorticoid antagonist, completely inhibited the increase in mRNA levels observed after exposure to dexamethasone (Fig 1B and 1C).

To examine whether the glucocorticoid-mediated effects required new protein synthesis, we pretreated A10 cells with cycloheximide (5 µg/mL) for 2 hours and then added dexamethasone to the medium for 12 hours. The yield of mRNA from the cycloheximide-treated cells was significantly increased compared with that in the cells not exposed to the protein synthesis inhibitor. Nevertheless, the proportion of the alternatively spliced signals was unchanged in the cycloheximide-treated cells. Dexamethasone failed to induce an increase in V_1a receptor mRNA in cells treated with cycloheximide (Fig 1B and 1C).

Effects of Glucocorticoids on V_1a Receptor mRNA Stability and Gene Transcription
We examined V_1a receptor mRNA stability by inhibiting new mRNA transcription with actinomycin D. After the cells had been incubated 12 hours with dexamethasone, actinomycin D (5 µg/mL) was added and the disappearance of V_1a receptor mRNA with time was measured by Northern blots. Fig 2 shows the effect of dexamethasone on V_1a receptor mRNA turnover. Half-life periods for the 2.8-, 2.1-, and 1.9-kb V_1a receptor mRNAs were 6.2, 6.8, and 6.6 hours, respectively, in the absence of dexamethasone; these half-life periods increased to 14.0, 14.8, and 14.4 hours (about 2.2-fold) in the presence of dexamethasone (data for the 2.8-kb transcript are shown in Fig 2). In addition, the effect of cycloheximide on V_1a receptor mRNA turnover was also examined, since cycloheximide affected the steady-state level of the V_1a receptor mRNA, as indicated in Fig 1. Fig 2 shows that the half-life periods for the 2.8-, 2.1-, and 1.9-kb transcripts increased to 9.4, 9.4, and 9.6 hours, respectively, on exposure to cycloheximide.

View larger version (32K): [in this window] [in a new window]   Figure 2. Blots and graph show effects of dexamethasone and cycloheximide on V1a receptor mRNA stability. V1a receptor mRNA stability was estimated by inhibition of gene transcription with actinomycin D (5 µg/mL). Decay of V1a receptor mRNA abundance was detected by Northern blots. Data are means of three separate experiments; results for 2.8-kb V1a receptor mRNA are shown in a regression curve.

We next examined the effect of dexamethasone on the transcriptional level using a nuclear run-off assay as reported previously.^{24 28} The results of the run-off assay were normalized to the transcription rate of the ß-actin gene, which was unchanged by exposure to dexamethasone. As shown in Fig 3, the transcription rate of the V_1a receptor gene was unchanged in the cells that had been exposed to dexamethasone for 12 hours compared with that of control cells. Similar results were obtained in the cells incubated with dexamethasone for 6 or 24 hours (data not shown). On the other hand, the relative transcription rate of the rat angiotensin II type 1 receptor gene was significantly increased (2.3±0.1-fold, n=3) in these dexamethasone-treated cells, as previously observed in cardiac fibroblasts²⁴ and vascular smooth muscle cells,⁶ confirming the validity of our nuclear run-off assay.

View larger version (62K): [in this window] [in a new window]   Figure 3. Blots show nuclear run-off assays of dexamethasone-induced changes in rat V1a receptor gene transcription rate. A10 cells were treated with dexamethasone (1 µmol/L) for 12 hours, and nuclei were isolated. Radiolabeled RNA was hybridized with linearized pBluescript (pBs) plasmid alone (15 µg), pBluescript containing rat V1a receptor cDNA (15 µg), rat angiotensin II type 1 receptor cDNA (AT1, 15 µg), or ß-actin cDNA (5 µg). Results are representative data from three separate experiments.

	Discussion

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We used an A10 rat vascular smooth muscle cell line to examine the regulation of the V_1a receptor gene by glucocorticoids. A10 cells express a high density of V_1a receptors and are well known as an ideal cell line for the study of vascular type V_1a receptor regulation.^{9 10} Incubation of A10 cells with a glucocorticoid resulted in a marked increase in the V_1a receptor protein, in agreement with a previous observation obtained in rat mammary tumor cells.²² In the present study we found that the A10 cells contain three different sizes of V_1a receptor mRNA and that glucocorticoid upregulates each of these mRNAs. This change in mRNA expression was due to an increase in mRNA stability rather than an elevated transcription rate. Morel et al¹⁷ showed that a single signal of 2.1-kb mRNA was exclusively expressed in rat liver, kidneys, spleen, and testis; they did not report the expression profile in A10 cells. Three different sizes of V_1a receptor mRNA were evident after washing at a high stringency and were upregulated similarly by glucocorticoid. There were no significant differences between the half-life periods of these mRNAs, and glucocorticoid stabilized each of these mRNAs equally. Although these data suggest that three different transcripts have a similar responsiveness to glucocorticoids, it remains to be determined whether these different transcripts are due to alternative polyadenylation or result from alternative splicing mechanisms.

For most genes regulated by steroids, gene expression is mainly influenced by a change in transcription rate,²⁹ but significant differences in mRNA stability have been reported. Glucocorticoids stabilize the growth hormone,³⁰ fibronectin,³¹ and phosphoenolpyruvate carboxykinase mRNAs³² and destabilize interleukin-1ß³³ and type 1 procollagen³⁴ mRNAs. Structures at the 3' end enhance or diminish the stability of the specific mRNAs: Glucocorticoids stabilize growth hormone mRNA by increasing the length of the poly(A) tail,³⁰ and the 3' noncoding region of phosphoenolpyruvate carboxykinase mRNA contains a glucocorticoid-responsive mRNA-stabilizing element.³² Of particular interest are the A plus U–rich regions, many of which contain the sequence AUUUA (in a single or, more frequently, a multiple repeat) upstream of and relatively near the poly(A) tail.³⁵ The rat V_1a receptor mRNA includes this sequence in its 3'-untranslated tail (S.M. et al, unpublished observation, 1995). Thus, different mechanisms appear to be involved in the stabilization process for various mRNAs, and the present study could not define which mechanism is responsible for the glucocorticoid-induced stabilization in rat V_1a receptor mRNA. The finding that cycloheximide affects the steady-state level of V_1a receptor mRNA by increasing its mRNA stability suggests that de novo synthesis of a destabilizing factor is involved in the mRNA degradation. The failure of dexamethasone to induce an increase in mRNA abundance on exposure to cycloheximide raises the possibility that dexamethasone upregulates V_1a receptor mRNA level by increasing synthesis of a putative stabilizing factor.

Gene transcriptional regulation by steroids requires the interaction of the hormone-intracellular receptor complex with cis-regulatory sequences.³⁶ The transcriptional induction by glucocorticoids through the glucocorticoid response element is generally rapid and does not require new protein synthesis.³⁷ Expression of the structurally related ß₂-adrenergic receptor is regulated by glucocorticoids at the gene transcriptional level.³⁸ For the ß₂-adrenergic receptor, mRNA abundance rises rapidly (occurring within 15 minutes), and the maximal accumulation occurs between 1 and 2 hours. In the present study the maximal increase in V_1a receptor mRNA accumulation was observed after a 12-hour exposure to glucocorticoids, and new protein synthesis was involved in the steady-state level as well as the glucocorticoid-induced increase in V_1a receptor mRNA. In addition, the nuclear run-off assay clearly established that the gene transcription of the V_1a receptor is not stimulated by glucocorticoids. Using the nuclear run-off assay, we have shown that the gene transcription of the angiotensin II receptor is upregulated by glucocorticoids in cardiac fibroblasts²⁷ and A10 cells (Fig 3). Expression of _1ß-adrenergic⁵ and ß₂-adrenergic³⁸ receptors has also been shown to be upregulated by glucocorticoids on the gene transcriptional level. Thus, the V_1a receptor gene may belong to a distinct group in seven transmembrane–type receptors with respect to the response to glucocorticoids.

In conclusion, we have demonstrated that glucocorticoids induce the expression of V_1a receptor mRNA and protein by increasing mRNA stability and that de novo protein synthesis is involved in this regulation. Although the established A10 smooth muscle cell line is derived from rat thoracic aorta and may not reflect with fidelity events in relevant vascular smooth muscles, the number of receptors and mRNA abundance remained increased even after a 48-hour exposure to glucocorticoids, suggesting that AVP could at least in part contribute to the enhancement of vascular responsiveness observed in patients with Cushing's syndrome.

	Acknowledgments

 
This study was supported in part by research grants from the Ministry of Education, Science, and Culture, Japan; Naito Research Foundation; and Kanae Research Foundation in Japan.

Received January 25, 1995; first decision March 23, 1995; accepted June 20, 1995.

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