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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 3 865-869
Copyright © 1997 by The Endocrine Society

Endocrinological Oncology

Angiotensin II Receptors in Cortical and Medullary Adrenal Tumors1

Giuseppe Opocher, Stefano Rocco, Margherita Cimolato, Barbara Vianello, Giorgio Arnaldi and Franco Mantero

Institute of Semeiotica Medica, University of Padua, Padua; and the Division of Endocrinology, University of Ancona, Ospedale di Torrette (G.A., F.M.), Ancona, Italy

Address all correspondence and requests for reprints to: Giuseppe Opocher, M.D., Istituto di Semeiotica Medica, Via Ospedale 105, 35128 Padua, Italy. E-mail: opocher{at}ipdunidx.unipd.it


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Several pieces of evidences suggest that angiotensin II (Ang II) has mitogenic effects, and a link between Ang II receptors and adrenal tumors can be suggested. In various adrenal tumors, aldosterone-producing adenoma (APA), Cushing’s adrenal adenomas (Cush), pheochromocytomas (Pheo), and adrenal carcinomas, we studied the density, affinity, and subtype of Ang II receptors. Ang II binding was tested in cell membrane homogenates. [125I]Ang II was used as ligand, and Losartan and CGP 42112 were used as selective Ang II type 1 and type 2 antagonists, respectively. In APA, Ang II receptor density was 178.5 ± 82.7 fmol/mg: however, due to the high degree of variability, the receptor density was not significantly higher than that in nontumorous adrenal cortex (59.3 ± 8.4 fmol/mg). In Cush, the receptor density (27.6 ± 8.2 fmol/mg; P < 0.05) was significantly lower than that in controls, whereas in Pheo and cortical carcinoma, Ang II binding was very low and in several cases almost undetectable. There was no remarkable difference in the Ang II receptor affinity among all tissues tested. The ratio between type 1 and type 2 Ang II receptors showed a large prevalence of type 1 in controls, APA, and three cases of Cush; in two cases of Cush, this ratio was reversed.

In conclusion, our data indicate that Ang II receptors are normally expressed in APA and can also be detected in Cush, whereas they have a very low density in Pheo and adrenal carcinoma. Therefore, Ang II receptors are not involved in the lack of response to Ang II that is characteristic of APA; additionally, a reduction of Ang II receptors can be associated with dedifferentiation or malignancy of adrenal tumors. Further investigation of the expression and functional characterization of Ang II receptors is required to better clarify their possible role in adrenal tumorigenesis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
TYPE 1 angiotensin II (Ang II) receptors (AT1) transduce most of the known actions of Ang II, including the steroidogenic and trophic actions on the adrenal zona glomerulosa as well as vasoconstriction (1, 2). This type of receptor belongs to the seven-transmembrane domain receptor family and is coupled with G proteins that inhibit cAMP synthesis and stimulate phospholipase. Very recently, two distinct subtypes, AT1a and AT1b, of the human AT1 have been cloned (3). Although AT1a and AT1b differ in the tissue distribution, receptor regulation, and signal transduction (4), the selective AT1 antagonist Losartan does not discriminate between the them.

Similarly to AT1, type 2 Ang II receptor (AT2) (5, 6) has seven membrane-spanning domains, although sequence homology with AT1 is low. The only signal transduction so far described for rat AT2, which has a 92.6% sequence homology with the human type, is the inhibition of phosphotyrosine phosphatase.

The possibility of a role of AT2 in the control of cell growth was suggested by the high receptor density detected during fetal development (7, 8), but other evidence suggests that Ang II is a growth factor-like agent that can induce hypertrophy as well as hyperplasia on target cells, mainly through AT1 activation (9, 10).

The presence of Ang II receptors in aldosteronomas was documented some years ago (11); however, subtype analysis was not available at that time. Ang II receptors are located not only in the zona glomerulosa, but also in the zona fasciculata (12) and adrenal medulla (13); only in the latter is there a prevalence of AT2 receptors. Differently from zona glomerulosa, the roles of Ang II receptors in the zona fasciculata and medulla have yet to be clarified. Very little is known about the link between Ang II receptors and other adrenal tumors.

Therefore, we studied the density, affinity, and subtype of Ang II in cell membranes obtained from eight aldosterone-producing adenomas (APA), five Cushing’s adrenal adenomas (Cush), six pheochromocytomas (Pheo), four cortisol-secreting adrenal carcinoma, and eight nontumorous adrenal cortexes (zona glomerulosa plus zona fasciculata).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The tissues investigated in the present study were taken from patients affected by the following adrenal tumors: APA, cortisol-producing adenoma, Pheo, and adrenal carcinoma (Table 1Go). The diagnoses were made on the basis of clinical, biochemical, and morphological data.


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  		Table 1. Clinical data of the patients in this study

 
In particular, patients with primary aldosteronism showed hypertension, suppressed PRA, high urinary aldosterone, high basal plasma aldosterone values that were unresponsive to upright posture and captopril administration, and evidence of adrenal mass at the computed tomography (CT) scan and/or adrenal scintigraphy; in the doubtful cases, selective adrenal venous catheterization was also performed. Among the eight cases of primary aldosteronism, one was highly significant for the presence of an aldosterone-producing renin-responsive adenoma (APRA) (14, 15); in fact, it showed the increase in plasma aldosterone during upright posture, the significant decrease after captopril administration, and a high response to low dose Ang II administration. Patients with Cushing’s syndrome presented clinical features of glucocorticoid excess, with high plasma and urinary cortisol values, unresponsivity to 8 mg dexamethasone and CRH infusion, and an adrenal mass at the CT and/or adrenal scintiscan.

Diagnosis of pheochromocytoma (five sporadic and one multiple endocrine neoplasm type 2a) was based on the finding of high urinary or plasma catecholamines, intermittent or stable hypertension, and an adrenal mass at the computerized adrenal tomography or nuclear magnetic resonance scanning, with a positive [123I]metaiodobenzylguanidine scintigraphy.

The patients affected by adrenal carcinoma presented a glucocorticoid excess syndrome. The visualization of adrenal mass and metastasis (in three cases) was achieved by CT scan or nuclear magnetic resonance scanning.

In all cases, surgery and histological examination confirmed the preoperative diagnosis.

Control samples were taken from the remaining nontumorous adrenal cortex in four cases of Pheo, two cases of Cushing’s syndrome, and one case of primary aldosteronism; normal adrenal gland samples were obtained also from one patient who underwent nephrectomy for kidney cancer (Table 1Go). Tissues were collected in liquid nitrogen immediately after surgery and stored at -80 C. The analysis of Ang II receptors was performed with minor modifications of the methods of Douglas et al. (16).

About 0.05 mm3 tissue was thawed, cleared of fat, and homogenized by Polytron in 15 mL 20 mmol/L sodium bicarbonate solution. After that, the homogenate was stirred on ice for 20 min., filtered through a 100-µm pore size nylon gauze, and then centrifuged at 100 x g for 10 min. The supernatant was centrifuged at 30,000 x g for 30 min, and the pellet was resuspended and homogenized with a glass-Teflon homogenizer in Tris-HCl-buffered medium (pH 7.4), which contained 5 mmol/L MgCl2 and 2 mmol/L ethyleneglycol-bis-(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid (16). The binding capacity of adrenal cell membranes (100–150 µg protein) was assayed by incubation with 0.2–0.3 nmol/L [125I]Ang II (native hormone; Amersham, Aylesbury, UK) in the Tris-HCl-buffered medium (pH 7.4), which contained 120 mmol/L NaCl and 0.2% BSA, and increasing concentrations (0–10 nmol/L) of cold Ang II. Nonspecific binding was determined in the presence of 1 mmol/L cold Ang II, and the subtype characterization was performed with Losartan and CGP 42112 (10-6-10-9 mol/L), which are selective AT1 and AT2 antagonists, respectively. The incubation (45 min at 22 C) was stopped by adding cold phosphate-buffered saline, and the bound radioactivity was separated by repeated centrifugation and measured in a {gamma}-counter. The receptor concentration and affinity were then calculated with Ligand software. The percentages of AT1 and AT2 receptors were calculated as a mean of at least three points of displacement; total displacement was normalized to 100%.

Statistical analysis

Results are expressed as the mean ± SEM. The significance of the data was calculated using the Bonferroni corrected ANOVA test; P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The Scatchard analysis of Ang II-binding sites showed a reliable presence of Ang II receptors in APA (mean, 178.5 ± 82.7), although a remarkable variability exists among the cases (ranging from 34.4–741.1 fmol/mg protein; Fig. 1Go). Raw data are reported in Table 2Go. The APRA showed a receptor density of 83.6 fmol/mg protein, comparable with the other cases. The mean affinity, expressed as Kd, ranged from 4.7–15.9 x 10-10 mol/L (mean, 8.6 ± 1.3). In APA, the use of the specific antagonists of Ang II receptor revealed a prevalence of AT1-binding sites, with minimal variations among the cases. The mean percentages of AT1 and AT2 were 73.0 ± 2.1% and 27.0 ± 2.1%, respectively. This was evaluated either by Scatchard analysis in separate assays (Fig. 2Go, top panel) or by examination of displacement curves (Fig. 2Go, bottom panel). A similar pattern was observed in APRA (AT1, 70.5%; AT2, 29.5%).



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  		Figure 1. Receptor density of Ang II receptors expressed in femtomoles per mg protein, calculated in cell membranes obtained from control adrenals (n = 8), APA (n = 8), Cush (n = 5), Pheo (n = 6), and adrenal carcinoma (n = 4). A significant reduction of receptor density was observed in Cush, Pheo, and adrenal carcinoma.

 

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  		Table 2. Raw data from the experiments performed in this study

 


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  		Figure 2. Representative experiments obtained from APA samples. A Scatchard plot of Ang II receptors in the presence of specific antagonists, Losartan (10-7 mol/L) and CGP 42112 (10-7 mol/L) is shown in the top panel. Displacement curves obtained with Losartan and CGP 42112 at various concentrations are shown in the bottom panel.

 
In control tissues, receptor density ranged from 26–89.8 fmol/mg protein (mean, 59.3 ± 8.4). The affinity was 6.2 ± 0.6 x 10-10 mol/L, and the distribution of AT1 and AT2 subtypes was 76.1 ± 5.5% and 23.8 ± 5.5%, respectively. The difference between aldosteronoma and controls did not reach significance because of the high degree of variability of the aldosteronoma sample.

In Cush, the receptor density was 27.6 ± 8.2 fmol/mg protein, a significantly lower value than in APAs and in control tissues, whereas the affinity was similar (Kd, 7.0 ± 1.0 x 10-10 mol/L). Two cases of Cush showed a reversed ratio between AT1 and AT2 (37% vs. 63% in one case and 35% vs. 65% in the other).

In Pheo the receptor density was very low; in two cases it was undetectable, whereas in the remaining four samples the mean was 5.0 ± 1.5. The affinity ranged from 5.5–18 x 10-10 mol/L (mean, 11.6 ± 3.6), and the receptors were mostly of the AT1 subtype.

In two cases of adrenal carcinomas no receptors were detected, and in the other two cases the density was very low (9.1 and 2.7 fmol/mL), with a low affinity.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Patients with idiopathic hyperaldosteronism have been defined as having a marked hypersensitivity to Ang II, whereas patients with APA are mainly Ang II unresponsive. Most patients with APA included in this study showed no response of aldosterone secretion after in vivo manipulation of endogenous Ang II, such as upright posture and captopril administration. This pattern was similar to that observed in aldosteronoma cells, where aldosterone production is only partially stimulated by Ang II, whereas it is greatly increased by ACTH (17). However, although aldosteronoma showed a reduced steroidogenic response after Ang II, specific Ang II receptors have been detected.

Our data confirm the finding of Bravo, who first demonstrated the presence of Ang II receptors in aldosteronoma cells (11); despite a certain degree of tumor heterogeneity, they showed a difference between APA and normal adrenal cortex. In addition, our results indicate that AT1 is the prevalent subtype in both APA and control adrenal; AT2 receptors were 10–20% of the total. Moreover, the data obtained in controls may be underestimated because, unlike APA, we had not a homogeneous tissue, but a mixture of zona glomerulosa, zona fasciculata, and zona reticulata cells.

The binding capacity of Ang II receptor despite partial resistance to the aldosterone-stimulating effects of Ang II suggests that the signal transmission machinery, i.e. receptor and G protein should be in some way altered in APA cells. Several receptor or G protein mutations have been found in other endocrine tissues, such as thyroid and pituitary tissues, leading to a constitutional increased activity. In primary aldosteronism, G protein mutations have not been shown, whereas analysis of the Ang II receptor gene has recently shown the absence of mutations along its coding sequence (18, 19). Therefore, a more detailed investigation of postreceptor events is necessary to clarify the apparent contradiction between Ang II receptors and the steroidogenic response of aldosteronoma cells.

Another aspect of interest is the possible relationship between Ang II and the induction of adrenal gland tumors. The mechanism by which Ang II exerts its growth factor activity on target cells has been partly elucidated. In vascular smooth muscle cells, Ang II binds to AT1 receptors and activates immediate early genes, such as c-fos, c-myc, c-jun, and growth factor genes, such as basic fibroblast growth factor, platelet-derived growth factor, and transforming growth factor-ß1 (TGFß1) (20, 21, 22). Cell growth depends on the balance of those factors. Particularly interesting is the role of TGFß1, which, once activated by Ang II, can reverse the hyperplastic or hypertrophic response in vascular smooth muscle cells (20). By modulating TGFß1 expression (10), Ang II could control, rather than stimulate, the growth of target cells.

Less is known in normal and tumoral human adrenal cells. However, in the human fetal adrenal, TGFß1 modulates the steroidogenic response (23) and inhibits the cell growth effect (24). This suggests that Ang II and TGFß1 play a role in the development of adrenal tumors.

A comparison of the results obtained in aldosteronoma with those obtained in fasciculata-derived adenoma, adrenal cortex carcinomas and pheochromocytomas may provide further information about the relationship between the presence of Ang II receptors and cellular growth and differentiation of the adrenal.

The presence of Ang II receptors in human fasciculata cells has been previously documented. In cortisol-secreting adenoma we showed the existence of Ang II receptors, although at a lower density than in glomerulosa adenoma and controls (zona glomerulosa plus zona fasciculata). Previously, Takaynasi et al. (25) showed AT1 receptor gene expression in a case of cortisol-secreting adenoma; our study extends this observation, suggesting that Ang II receptors are also expressed at the protein level. Although the comparison with pure normal zona fasciculata is not available, and a small number of patients have been studied to date, it is probable that Ang II receptor plays a role in these tissues.

In two patients there was a prevalence of AT2 receptor; this is a new observation that remains unclear, but it could be relevant in the understanding of a role of AT2 receptors in the control of cell growth in these tumors.

In Pheo, Ang II receptor density was very low in four cases and undetectable in two, whereas affinity was lower than that in normal adrenal cortex; this confirms previous studies (13, 25) in a larger number of cases. This is in contrast with the data recently published by Tsuzuki et al. (26), who cloned the gene sequence of human type 2 Ang II receptor. Despite the lack of an appropriate internal control, as normal adrenal medulla should have been, this finding is important because autoradiography showed a high density of AT2 receptors in normal medulla. In rat Pheo cells, AT2 receptor stimulation mediates programmed cell death, suggesting that this receptor can play an important role in developmental biology and pathophysiology (26). Thus, the lack of Ang II receptors in human pheochromocytoma, we have found, may be more than a marginal observation.

Also, in adrenal carcinoma, Ang II receptors were almost undetectable. As our receptor assay has been performed in the absence of specific protease inhibitors, it is possible that a different proteolytic activity of the Pheo and carcinoma samples affects Ang II degradation and causes underestimation of the receptor density. However, we have some preliminary data obtained by reverse transcription-PCR, showing that in Pheo, AT1 and AT2 messenger ribonucleic acids are virtually absent (data not shown). This indirectly supports the idea that adrenal cortex malignancy is associated with failure to express Ang II receptors. In our study it is noteworthy that in the two cases in which we did not find any binding, the progression of the cancer was very impressive, and both patients had a poor prognosis. The disappearance of Ang II binding might be related to malignancy and dedifferentiation. This can be relevant, as Ang II receptor activation stimulates the expression of TGFß1 (10), which can act as an antagonist of other growth factors (27). Preliminary data (28) indicate a deficient expression of TGFß1 in adrenal carcinoma, and this suggests that a low number of Ang II receptors in adrenal cortical cells play a role in the development of this tumor.

In conclusion, our data indicate that Ang II receptors are normally expressed in APA and can also be detected in Cush, whereas they have a very low density in Pheo and adrenal carcinoma. Therefore, Ang II receptors are not involved in the lack of response to Ang II that is characteristic of APA; additionally, a reduction of Ang II receptors can be associated with dedifferentiation or malignancy of adrenal tumors. Further investigation of the expression and functional characterization of Ang II receptors is required to better clarify their role in adrenal tumorigenesis.


   Footnotes
 
1 Presented in part at the Sixth Conference on the Adrenal Cortex, September 21–24, 1994, Ardmore, OK. This work was supported by CNR Grant 93.00723.CT04 and Murst 40 and 60% grants (to G.O.), and AIRC Grant 465/94 (to F.M.). Back

Received January 11, 1996.

Revised September 26, 1996.

Accepted November 13, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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