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Endocrinology Vol. 138, No. 10 4176-4180
Copyright © 1997 by The Endocrine Society

ARTICLES

Growth Hormone Regulates AT-1a Angiotensin Receptors in Astrocytes1

Bruce Wyse and Conrad Sernia

Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia

Address all correspondence and requests for reprints to: Dr. Conrad Sernia, Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia. E-mail: C.Sernia{at}mailbox.uq.oz.au


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The hypothesis, based on previous in vivo data, that angiotensin AT1 receptors are regulated by GH or insulin-like growth factor I (IGF-I) has been investigated in this study using primary cultures of rat astrocytes as a model of AT1 receptor expression. At a dose of 1 ng/ml GH, there was an increase in AT1 density within 4 h and a maximum increase of 361 ± 57% of the control value at 12 h. At 24 h, receptor density was still 176 ± 23% that in the control. Astrocytes incubated with 1 ng/ml rat IGF-I for 24 h showed no change in AT1 receptor density. Reverse transcriptase-PCR was used to show that astrocytes express both the AT1a receptor subtype and, to a much lesser extent, the AT1b subtype. Treatment with 1 ng/ml recombinant bovine GH for 12 h increased the messenger RNA of the AT1a receptor by 170%, without affecting the AT1b receptor. Inhibition of protein synthesis by cycloheximide and of transcription by the adenosine analog dichlororibofuranosylbenzimidazole both prevented the increase in AT1 receptor density following GH treatment, indicating that the action of GH is transcriptional. In summary, we have shown that GH up-regulates, directly and not via IGF-I, angiotensin receptors of the AT1a subtype in astrocytes by a transcriptional mechanism. The long latency of the response and the dependency on transcription relegate the AT1a gene to the class of GH-regulated genes identified as delayed stable genes. This mechanism of AT1 activation may be one way in which GH activates the renin-angiotensin system and initiates consequential cardiovascular and angiogenic effects.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CARDIOVASCULAR disease is common in patients with acromegaly, a condition characterized by excess GH (1). An activation of the renin-angiotensin-system (RAS) is among the hormone systems that are inappropriately stimulated by the excess of GH and ultimately contributes, by poorly understood mechanisms, to the development of cardiovascular disease (2, 3, 4). In our previous study with genetically GH-deficient Lewis rats, evidence was found for an up-regulation by GH of kidney, liver, and adrenal angiotensin II (AngII) receptor densities (5), thus implicating the expression of AngII receptors as a point of interaction between GH and the RAS. However, in that study we did not pursue the nature of the GH-RAS interaction beyond noting total AngII density changes after the injection of suboptimal doses of recombinant GH.

The actions of AngII are mediated by AT1 and AT2 subtypes of the receptor (6). Cloning and sequencing of rat AngII receptors has shown distinct genes coding for AT1a and AT1b receptors (7). The coding regions and amino acid sequences of these AT1 receptors show a high homology, whereas the 5'-flanking promoter regions show only 36% homology. This suggests major differences in the way AT1a and AT1b genes are regulated (8). Cardiovascular functions appear to involve largely the AT1 subtypes, found in abundance in blood vessels, heart, kidney, liver, adrenal, pituitary, and brain (9), all of which are involved in pressor, electrolyte, and fluid homeostasis. As GH treatment affects liver, kidney, and adrenal AngII receptors, one or both of the AT1 receptor genes appear to be the targets of GH regulation, although it would be premature based on the present limited evidence to exclude any of the AngII receptor subtypes.

In this study we investigated the hypothesis that GH regulates AT1 receptors. We avoided the limitations inherent in whole animal studies by using primary cultures of astrocytes from the rat hypothalamus, an area involved in cardiovascular regulation. These cells express AT1 receptors abundantly and have been used previously in angiotensin receptor studies (10, 11); they are responsive to GH and insulin-like growth factor I (IGF-I) (12, 13), and they are easily cultured in supplemented serum-free medium (14). Using this astrocyte model, we examined the effect of recombinant bovine GH (rbGH) and recombinant human IGF-I (rhIGF-I) on the expression of AT1 receptor density, the latency of hormone action, and the dependency of the response on hormone concentration. We also obtained molecular information on the actions of GH by measuring changes in AT1 messenger RNA (mRNA) and the effects of inhibiting translation or transcription on receptor AT1 density.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental design
Cultures of astrocytes were prepared essentially as described previously with some modifications (14). In brief, cultures were prepared from subcortical brain tissue from newborn Wistar rats. The tissue was dispersed by trypsinization (0.125% trypsin-Ca2+ in DMEM) and inoculated into 75-cm2 tissue culture flasks with DMEM containing 10 mM NaHCO3, 25 mM HEPES, and 10% FCS at a density of 6 x 106 cells/flask. After 3-day incubation at 37 C with 2.5% CO2 in air, medium was replaced with glucose-free DMEM (10% FCS) containing 25 mM sorbitol. After 7-day incubation, cells were resuspended and plated into six-well plates at a density of 2 x 105 cells/9.5-cm2 well. They were cultured for an additional 10 days in glucose DMEM (with 10% FCS) before experimentation. We found that cultures grown for 7 days in sorbitol-containing medium consisted of more than 99% astrocytic cells, as determined by the immunohistochemical procedure for glial fibrillary acidic protein described previously (12). Cells were then starved of serum for 24 h, and the effect of GH on AngII receptor content was examined by incubating cells for an additional 24 h with 0 (control group), 0.1, 1, 10, or 100 ng/ml rbGH (Monsanto, Chesterfield Village, MO). The observation that 1 ng/ml GH up-regulates AngII receptors was tested in a series of time experiments in which cells were incubated for 0, 0.5, 1, 2, 4, 8, 12, and 24 h with (treated group) or without (control group) 1 ng/ml rbGH. Similar experiments were performed with cells treated with rhIGF-I (1 ng/ml; Pharmacia, Sydney, New South Wales, Australia).

Subsequent experiments, investigated the mechanism by which GH regulates AngII receptor. Cycloheximide (CYC; Sigma Chemical Co., St. Louis, MO; 3.6 µM), an inhibitor of protein synthesis or the adenosine analog 5,6-dichlorobenzimidazole riboside (DRB; Sigma; 75 µM), an inhibitor of transcription, was added to cells in serum-free medium or in serum-free medium containing 1 ng/ml GH. After 12 h, AngII receptor content was measured.

RRA
RRAs were performed in triplicate on cultures in six-well plates. After washing with 1 ml Dulbecco’s PBS, pH 7.2, at 22 C, 0.6 ml Dulbecco’s PBS, 0.6% BSA, [125I]Sar1,Ile8-AngII (50,000 cpm), and varying concentrations of Sar1,Ile8-AngII ranging from 0–200 nmol/liter were added and incubated for 1 h. This length of incubation is sufficient to establish steady state binding conditions (results not shown). Unbound peptide was removed with five 2-ml washes in ice-cold PBS (pH 7.4) containing 0.6% BSA, and cells were subsequently digested in 500 µl 1 M NaOH. Residual protein was washed from each well with 500 µl water, and radioactivity bound to the cells was quantitated by {gamma}-counting (model 1277, LKB, Rockville, MD). Nonspecific binding was determined in the presence of 1 µM Sar1,Ile8-AngII. Protein content was quantitated using Coomassie blue (15), and specific binding was expressed per mg protein. Binding data were analyzed by Ligand (Biosoft, Cambridge, UK) to determine the affinity, Ka, and density of binding sites (Bmax).

RT-PCR
Total RNA was extracted from astrocytes, liver, adrenal, kidney, and heart by the method of Chomczynski and Sacchi (16). RNA was measured by spectrophotometry at 260 nm and frozen at -80 C until used. Total RNA (2 µg/µl) was reverse transcribed using Moloney murine leukemia virus reverse transcriptase (Promega, Madison, WI) and an oligo(deoxythymine)15 primer. The complementary DNA (cDNA) obtained from the reverse transcription was amplified by PCR using the following published primer sequences: AT1a receptor: sense, 5'-GCACACTGGCAATGTAATGC-3'; antisense, 5'-GTTGAACAGAACAA-GTGACC-3; AT1b receptor: sense, 5'-GCCTGCAAGTGAAGTGATTT-3'; antisense, 5'-TTTAACAGTGGCTTTGCTCC-3' (17); AT2 receptor: sense, 5'-TCTGGCTGTGGCTGACTT-3'; antisense, 5'-CAAGACTTGGTCACGGGT-3' (18); and glyceraldehyde-3-phosphate dehydrogenase (GAPDH): sense, 5'-TCCCTCAAGATTGTCAGCAA-3'; antisense, 5'-AGATCCACAACGGATACATT-3'. With these primers, the lengths of the PCR products were 385, 204, 511, and 309 bases, respectively. The thermal cycle profile for AngII receptor subtypes and the housekeeping marker GAPDH involved a three-step amplification; 35 cycles of 94 C for 60 sec, 58 C for 60 sec, and 72 C for 75 sec, followed by a final extension step 72 C for 10 min. The PCR product was separated on a 1% agarose gel containing ethidium bromide and visualized under UV light. The image was captured with a high resolution CCD camera, and the density of the bands was quantified by the computer image analysis program MD30+ (Leitz-Wild, Brisbane, Queensland, Australia). Each step of the RT-PCR was optimized for linearity. Thus, the quantity of PCR product was related to the quantity of cDNA template used and the number of cycles. The amount of product separated on the agarose gel was also optimized to fall in the linear range of the integrated optical density of the captured image. The adrenal gland, which expresses all AngII receptor subtypes, was used as a positive control in the RT-PCR. Finally, each PCR product was sequenced (Sequencer model 373A, version 1.2.0, Applied Biosystems, Foster City, CA) and confirmed as being identical to the expected cDNA sequence.

Statistics
All results were expressed as the group ± SE. Comparisons of group means were made by ANOVA with Dunnett’s multiple comparison test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In initial experiments, AngII RRAs with [125I]Sar1,Ile8-AngII were performed on astrocyte cultures that had been incubated with 0–100 ng/ml rbGH for 24 h. As shown in Fig. 1aGo, AngII receptor density increased to 176 ± 23% of the control value (P < 0.01) at a dose of 1 ng/ml and tended to remain high at 10 ng/ml (135 ± 23% of control) and 100 ng/ml rbGH (115.7 ± 31% of control). Using the optimal dose of 1 ng/ml rbGH, we observed that an incubation time of at least 4 h was required for receptor density to increase (183 ± 51% of control; P < 0.01; Fig. 1bGo). The response reached a maximum at 12 h (360.6 ± 57% of control; P < 0.01) and then decreased at 24 h.



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  		Figure 1. Effect of GH, expressed as a percentage of the control value, on the density of AngII receptors in astrocyte cultures. Confluent quiescent cultures of astrocytes were treated with rbGH (a) at concentrations of 0–100 ng/ml for 24 h or a constant concentration of 1 ng/ml rbGH (b) for a range of times up to 24 h. For the data in b, cultures incubated without GH for the same range of times were used as controls for the corresponding GH-treated group. Receptor density was then determined by radioligand assay. Data are shown as the mean ± SE for six experiments. Group means were compared with the first group (no rbGH or zero time) by Dunnett’s t test: *, P < 0.05; **, P < 0.01.

 
Scatchard plot analyses of [125I]Sar1,Ile8-AngII binding in astrocytes incubated at the optimal conditions of 12 h with 1 ng/ml rbGH are shown in Fig. 2Go. This figure shows the large increase in Bmax in the GH-treated cells (indicated by the intercept on the x-axis), whereas the Ka of the ligand-receptor interaction (represented by the slope of the linear fit) remained unchanged. These data indicate that GH is affecting the number of receptors and not the ligand-binding properties.



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  		Figure 2. A representative Scatchard analysis of the binding of [125I]Sar1,Ile8-Ang II to control astrocytes ({square}) or astrocytes treated with 1 ng/ml rbGH ({blacksquare}) for 12 h. The receptor density (indicated by the x-intercept) was increased markedly by GH without changing the ligand affinity (Ka), as indicated by the similar slopes (12 liters/pmol for control; 11 liters/pmol for GH).

 
The observed effect of rbGH treatment on astrocyte AngII receptors could have been mediated by a stimulation of astrocyte IGF-I secretion rather than by rbGH itself. This possibility was tested by treating astrocytes with 1 ng/ml IGF-I over a 24-h period. The AngII receptor density over 2 (83.1 ± 35% of control), 4 (86 ± 17% of control), 8 (79.9 ± 24% of control), 12 (96 ± 14% of control), or 24 h (84 ± 48% of control) did not change significantly.

Data showing changes in receptor density alone are not evidence of changes in AT1 receptor biosynthesis. Moreover, ligand binding studies cannot distinguish between AT1a and AT1b, and they are not definitive for the absence of AT2 receptors. Hence, we proceeded to use RT-PCR for the detection of mRNA species for AT1a, AT1b, and AT2 receptors and the housekeeping marker GAPDH. The relative expression levels of the AT1a, AT1b, and AT2 receptors for the adrenal gland and primary astrocyte cultures are shown in Fig. 3Go. The intensity of the bands at their respective 385 bases for the AT1a receptor position (204 bases for the AT1b receptor and 511 bases for AT2 receptor) reflect their relative levels of expression. As expected, the adrenal expresses the AT1a (lane 1), AT1b (lane 3), and AT2 (lane 5) receptors. Astrocyte cultures were shown to predominantly express the AT1a receptor (lane 2), with a small signal for the AT1b receptor (lane 4) and no expression for the AT2 receptor (lane 6).



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  		Figure 3. The detection of mRNA for AngII receptor subtypes using amplification by RT-PCR, separation of products by gel electrophoresis, and visualization by staining with ethidium bromide. The figure shows RT-PCR products for the AT1a (lanes 1 and 2), AT1b (lanes 3 and 4), and AT2 (lanes 5 and 6) receptors of the adrenal glands and astrocyte cultures. Only AT1a (lane 2) and, to a lesser extent, AT1b (lane 4) were found in astrocytes; no AT2 (lane 6) was present. The adrenal gland was used as a positive control and showed the AT1a (lane 1), AT1b (lane 3), and AT2 (lane 5) receptor subtypes. Further confirmation of each PCR product was obtained by sequencing and verifying the sequence by comparison with the expected cDNA sequence.

 
Figure 4Go shows the AT1a and AT1b receptor mRNA expression (relative to the internal control, GAPDH mRNA) in astrocytes exposed to 0–100 ng/ml rbGH for 12 h. As in astrocyte AngII binding studies, treatment with rbGH (1 ng/ml) resulted in a dose-response increase in AT1a mRNA expression at 0.01 (0.73 ± 0.04) and 0.1 (0.92 ± 0.07) ng/ml GH and a maximum increase at 1 (0.95 ± 0.10) ng/ml GH, followed by decreases toward the control value (0.573 ± 0.02) at doses of 10 (0.75 ± 0.02) and 100 (0.70 ± 0.08) ng/ml GH (Fig. 4aGo). Doses of 0.01 (0.08 ± 0.03), 0.1 (0.09 ± 0.02), 1 (0.09 ± 0.03), 10 (0.07 ± 0.01), and 100 (0.09 ± 0.01) ng/ml GH did not alter the level of astrocyte AT1b receptor mRNA expression from the control value (0.1 ± 0.04; Fig. 4bGo).



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  		Figure 4. Effect of treating astrocytes with GH on the expression of AT1a and AT1b subtypes mRNA, as measured by RT-PCR. Astrocyte cultures were treated for 12 h with rbGH up to a concentration of 100 ng/ml, and then the expression of AT1a (a) and AT1b (b) was measured and quantified as a ratio of the marker GAPDH mRNA. Insets are representative ethidium bromide-stained images of respective RT-PCR products for AT1a and GAPDH. Data are shown as the mean ± SE for five experiments. Group means were compared with the control group (no rbGH) by Dunnett’s t test: **, P < 0.01.

 
To determine at which biosynthetic stage GH regulates AngII receptors, cells were exposed to control or GH medium containing either DRB, to arrest transcription, or CYC, to inhibit protein synthesis for 12 h (Fig. 5Go). As expected, GH (101 ± 35 fmol/mg protein) alone significantly increased the AngII receptor level above control values (45 ± 9 fmol/mg protein). AngII receptor density did not differ between cells treated with GH in the presence DRB (12 ± 4 fmol/mg protein) or CYC (23 ± 8 fmol/mg protein) and cells treated with DRB (25 ± 5 fmol/mg protein) or CYC (23.6 ± 8 fmol/mg protein) alone.



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  		Figure 5. Effects of inhibitors of transcription and translation on the expression of AngII receptor density by astrocyte cultures. Quiescent astrocyte cultures were either left untreated for 12 h (CTRL) or were treated with 1 ng/ml rbGH (+GH); the inhibitor of transcription, DRB, in the absence (DRB) or presence (DRB+GH) of rbGH; or CYC, an inhibitor of protein synthesis, in the absence (CYC) or presence (CYC+GH) of rbGH. AngII receptor density was measured by radioligand assay. Data are shown as the mean ± SD for three experiments. Group means were compared with the control group (CTRL) by Dunnett’s t test: **, P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study investigated the roles of GH and IGF-I in the regulation of AT1 receptor expression. Isolated astrocyte cells from the hypothalamic area of the rat brain were used as a model system because of their abundant AT1 receptor expression (19) and their responsiveness to GH and IGF-I (12, 13). We established by RT-PCR of AT1a, AT1b, and AT2 receptors that our cultures indeed expressed AT1 and not AT2 receptors, and that about 85% of the AT1 receptors were of the AT1a subtype.

Treatment of astrocytes with 1 ng/ml rbGH for 0–24 h increased receptor density from 4 h onward, with a peak at 12 h. Repeating the same experiment while substituting IGF-I for GH did not increase receptor density, indicating that the observed action of GH is direct and not mediated by IGF-I. Using the peak response time of 12 h, the increases in receptor density were shown to vary with the concentration of GH, with a maximum response at 0.1 ng/ml to 1 ng/ml. As is typical of systems regulated by GH, further increases in GH to 10 and 100 ng/ml resulted in submaximal responses. The long delay of 4 h for a response to GH is more consistent with an effect on transcription than with faster events involving translation, posttranslational receptor recycling, and degradation. By measuring the relative changes in AT1a and AT1b mRNA during GH treatment, it was found that the mRNA for AT1a reflected qualitatively the changes in receptor density without any change in the AT1b mRNA. These data suggest that GH selectively regulates the AT1a receptor by mechanisms that change the abundance of mRNA, rather than by posttranslational mechanisms such as receptor recycling. This dependence on translation was further shown by the effective and complete block of GH action with the inhibition of translation by cycloheximide. It is also unlikely that stabilization of AT1a mRNA via nontranscriptional events could explain the increase in AT1a mRNA, because the inhibition of transcription by the adenosine analog DRB also completely inhibited the action of GH on AT1 receptor density.

GH-regulated genes have been classified according to the temporal pattern of transcriptional response (20) into immediate early genes, immediate stable genes, delayed transient genes, and delayed stable genes. The first two classes are induced within 30 min and are cycloheximide insensitive. The latter two classes take longer to induce and are cycloheximide sensitive. The AT1a gene clearly belongs to the class of delayed stable genes, as it takes hours for its induction, and the activation is stable over many hours and is dependent on protein synthesis. Other examples of this type of GH-regulated gene are the GLUT-1 glucose transporter (21), the low density lipoprotein receptor (22), and cytochrome P450 (23).

The mechanisms by which GH regulates transcription of target genes are presently not known in detail. The transcription factors C/EBP, activating protein-1 (AP-1), and STAT are activated by GH (24, 25, 26, 27), and they have been shown to mediate GH transcriptional activation (28). The STAT sites are generally associated with immediate early gene activation by GH (29), and therefore, their relevance to the activation of delayed stable genes such as the AT1a receptor may be minimal. It is also pertinent to note that the amplitude of c-fos transcriptional activation by GH (2- to 2.5-fold) (29) and thus of AP-1 induction (30) is comparable to the 1.7-fold increase in AT1a mRNA in this study. Response elements for both C/EBP and AP-1 have been noted for the AT1a gene (8). On this evidence and by analogy with other GH-regulated genes, the transcription factors C/EBP and AP-1 should be considered in future studies as strong candidates in the mediation of the transcriptional effects of GH on the AT1a gene.

The functional implications of GH regulation of AT1a receptors in astrocytes are at this stage largely a matter of conjecture, as little is known about the roles of astrocyte AngII receptors. AngII stimulates the release of PGs from rat astrocytes (31), and there is also evidence for an involvement in growth (32). However, there are known actions mediated by neuronal AngII receptors. For example, AngII stimulates catecholaminergic activity in the brain and in autonomic peripheral nerves that serve various neuroendocrine and vasopressor functions (33, 34). These would be expected to be exaggerated by excess GH and muted by insufficient GH, which could, in turn, lead to parallel changes in cardiac and vascular responses. A similar modulation of cardiovascular function would be expected from GH regulation of AT1a receptors in the vasculature, heart, and kidneys. Indeed, this relationship between GH and AT1a receptors could be a factor in the lower blood pressure and lower adrenergic responses of vascular tissue in GH-deficient rats and their partial restoration by GH treatment (35). A further pertinent functional implication of our results relates to the regulation of tissue growth and extracellular structure. If, as current data indicate (36), the angiogenic actions of AngII in renal, cardiac, and vascular tissues are mediated by the AT1 subtype, and the secretion of extracellular matrix proteins is also regulated by the AT1a receptor, then disturbances in GH secretion or action would, via AT1a receptors, adversely alter the structure of these same tissues.

In summary, these results show that primary astrocytes derived from the hypothalamus/thalamus area express predominantly AT1a receptors, which are directly up-regulated by GH and are not mediated by IGF-I. The response is time and dose dependent and is exerted at the transcriptional level of AT1a receptor expression. These observations support a role for the brain, in addition to the contribution of the peripheral RAS, in the development of cardiovascular disease in situations of inappropriate GH secretion.


   Acknowledgments
 
We are grateful to Dr. Peter Koopman, Center for Molecular Biology, for the sequencing of PCR products.


   Footnotes
 
1 This work was supported by grants (to C.S.) from the National Heart Foundation of Australia and the National Health and Medical Research Council. Back

Received February 20, 1997.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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