Aldosterone, secreted by the adrenal zona glomerulosa, enhances sodium retention, thus increasing blood volume and pressure. Excessive production of aldosterone results in high blood pressure and contributes to cardiovascular and renal disease, stroke and visual loss. Hypertension is also associated with obesity, which is correlated with other serious health risks as well. Although weight gain is associated with increased blood pressure, the mechanism by which excess fat deposits increase blood pressure remains unclear. Several studies have suggested that aldosterone levels are elevated with obesity and may represent a link between obesity and hypertension. In addition to hypertension, obese patients typically have dyslipidemia, including elevated serum levels of very low-density lipoprotein (VLDL). VLDL, which functions to transport triglycerides from the liver to peripheral tissues, has been demonstrated to stimulate aldosterone production. Recent studies suggest that the signaling pathways activated by VLDL are similar to those utilized by AngII. Thus, VLDL increases cytosolic calcium levels and stimulates phospholipase D (PLD) activity to result in the induction of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression. These effects seem to be mediated by the ability of VLDL to increase the phosphorylation (activation) of their regulatory transcription factors, such as the cAMP response element-binding (CREB) protein family of transcription factors. Thus, research into the pathways by which VLDL stimulates aldosterone production may identify novel targets for the development of therapies for the treatment of hypertension, particularly those associated with obesity, and other aldosterone-modulated pathologies.
Ying-Ying Tsai, William E Rainey, and Wendy B Bollag
Kelly De Sousa, Alaa B Abdellatif, Rami M El Zein, and Maria-Christina Zennaro
Primary aldosteronism (PA) is the most common form and an under-diagnosed cause of secondary arterial hypertension, accounting for up to 10% of hypertensive cases and associated to increased cardiovascular risk. PA is caused by autonomous overproduction of aldosterone by the adrenal cortex. It is mainly caused by a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Excess aldosterone leads to arterial hypertension with suppressed renin, frequently associated to hypokalemia. Mutations in genes coding for ion channels and ATPases have been identified in APA, explaining the pathophysiology of increased aldosterone production. Different inherited genetic abnormalities led to the distinction of four forms of familial hyperaldosteronism (type I to IV) and other genetic defects very likely remain to be identified. Somatic mutations are identified in APA, but also in aldosterone-producing cell clusters (APCCs) in normal adrenals, in image-negative unilateral hyperplasia, in transitional lesions and in APCC from adrenals with bilateral adrenal hyperplasia (BAH). Whether these structures are precursors of APA or whether somatic mutations occur in a proliferative adrenal cortex, is still a matter of debate. This review will summarize our knowledge on the molecular mechanisms responsible for PA and the recent discovery of new genes related to early-onset and familial forms of the disease. We will also address new issues concerning genomic and proteomic changes in adrenals with APA and discuss adrenal pathophysiology in relation to aldosterone-producing structures in the adrenal cortex.
John M C Connell and Eleanor Davies
Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific ‘aldosterone-induced’ proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety of actions of aldosterone that contribute to blood pressure homeostasis. These include key actions on endothelial cells and on cardiac tissue.
There is also evidence that aldosterone can be synthesised in other tissues; the most convincing evidence relates to the central nervous system. However, suggestions that aldosterone is produced in the heart remain controversial, and adrenal derived aldosterone is the principal source of circulating and locally available hormone.
Recent studies have shown major therapeutic benefits of mineralocorticoid receptor antagonism in cardiac failure, which emphasise the importance of aldosterone in causing adverse cardiovascular pathophysiological effects. Additional evidence demonstrates that aldosterone levels predict development of high blood pressure in normotensive subjects, while it is now clear that increased aldosterone action contributes to hypertension and cardiovascular damage in approximately 10% of patients with established hypertension.
These new findings highlight the role of aldosterone as a key cardiovascular hormone and extend our understanding of its role in determining adverse cardiovascular outcomes.
A L Markel, O E Redina, M A Gilinsky, G M Dymshits, E V Kalashnikova, Yu V Khvorostova, L A Fedoseeva, and G S Jacobson
The functions of the hypothalamic adrenal cortical and sympathetic adrenal medullary systems were studied in rats with inherited stress-induced arterial hypertension (ISIAH strain). A characteristic feature of the ISIAH strain is an increase in arterial blood pressure measured both under basal conditions and after restraint stress in particular. In the control ISIAH rats, the basal plasma ACTH concentration was slightly lower than that in the normotensive Wistar albino Glaxo (WAG) rats, and no differences were found in plasma corticosterone. However, the 0.5-h restraint stress produced higher activation of the adrenal cortex in the ISIAH rats. Gluco- and mineralocorticoid responses to the blood volume reduction stresses and ACTH and corticosterone responses to social stress were stronger in the ISIAH than in the control WAG rats. An increase in epinephrine content in adrenals in the basal state and enhanced response of the sympathetic adrenal medullary system to handling stress were observed in the ISIAH rats. Restraint stress produced significantly higher expression of genes encoding corticotropin-releasing hormone-mRNA in hypothalamus and proopiomelanocortin-mRNA in pituitary in the ISIAH than in the WAG rats. Restraint stress produced a decrease in glucocorticoid receptor (GR) gene expression (GR-mRNA) in hippocampus in the ISIAH, but not in the WAG rats. A persistent increase in tyrosine hydroxylase-mRNA in adrenals of the ISIAH rats was found. It is concluded that the ISIAH rat strain is an appropriate model of stress-sensitive hypertension with the predominant involvement of the hypothalamic adrenal cortical and sympathetic adrenal medullary systems in its pathogenesis.
Yewei Xing, Michael A Edwards, Clarence Ahlem, Mike Kennedy, Anthony Cohen, Celso E Gomez-Sanchez, and William E Rainey
The adrenal glands are the primary source of mineralocorticoids, glucocorticoids, and the so-called adrenal androgens. Under physiological conditions, cortisol and adrenal androgen synthesis are controlled primarily by ACTH. Although it is well established that ACTH can stimulate steroidogenesis in the human adrenal gland, the effect of ACTH on overall production of different classes of steroid hormones has not been defined. In this study, we examined the effect of ACTH on the production of 23 steroid hormones in adult adrenal primary cultures and 20 steroids in the adrenal cell line, H295R. Liquid chromatography/tandem mass spectrometry analysis revealed that, in primary adrenal cell cultures, cortisol and corticosterone were the two most abundant steroid hormones produced with or without ACTH treatment (48 h). Cortisol production responded the most to ACTH treatment, with a 64-fold increase. Interestingly, the production of two androgens, androstenedione and 11β-hydroxyandrostenedione (11OHA), that were also produced in large amounts under basal conditions significantly increased after ACTH incubation. In H295R cells, 11-deoxycortisol and androstenedione were the major products under basal conditions. Treatment with forskolin increased the percentage of 11β-hydroxylated products, including cortisol and 11OHA. This study illustrates that adrenal cells respond to ACTH through the secretion of a variety of steroid hormones, thus supporting the role of adrenal cells as a source of both corticosteroids and androgens.
M Reincke, F Beuschlein, G Menig, G Hofmockel, W Arlt, R Lehmann, M Karl, and B Allolio
The recent cloning of the ACTH receptor (ACTH-R) gene allows investigation of the tissue localization and relative abundance of ACTH-R mRNA in normal and neoplastic adrenal cortex. Using in situ hybridization (ISH) we studied the expression of ACTH-R mRNA in four adult adrenals of brain-dead patients, two cortisol-producing adenomas (CPA), three aldosterone-producing adenomas (APA), one non-functional adenoma (NFA), and three carcinomas. The results were compared with the mRNA expression of key steroidogenic enzymes and of the glucocorticoid receptor (GR) mRNA using Northern blotting. In adult adrenals, messenger RNA encoding ACTH-R was localized in all three zones of the adrenal cortex, in accordance with the stimulatory role of ACTH on mineralocorticoid, glucocorticoid and adrenal androgen secretion. In comparison, expression of side-chain cleavage enzyme (P450scc) showed a similar tissue distribution with mRNA abundance in all three zones, whereas 17-hydroxylase/17-20 lyase (P450c17) mRNA expression was only detected in the zona fasciculata and zona reticularis. All CPAs and APAs expressed significant levels of ACTH-R mRNA whereas an NFA showed low expression of ACTH-R mRNA. Two of three adrenocortical carcinomas expressed ACTH-R mRNA. Northern analysis using dot blot was employed to quantify ACTH-R and GR mRNA expression and confirmed the ISH data: ACTH-R mRNA expression was high in CPAs (275 and 195% vs 100 +/- 25% in adult adrenals), APAs (127, 200 and 221%) and two carcinomas (99 and 132%), but low in the NFA (7%) and in an androgen secreting carcinoma (16%). GR mRNA expression was high in the NFA (195%) and in two of three carcinomas (93, 188, 227%). We conclude that ACTH-R mRNA is upregulated in functional adenomas by yet unidentified mechanisms. The tissue distribution of ACTH-R and P450 enzyme mRNA expression is highly variable in neoplastic adrenals and does not allow a clear differentiation between benign and malignant tumors.
R Salemi, JG McDougall, KJ Hardy, and EM Wintour
In vivo and in vitro studies have shown conflicting effects of adrenomedullin (ADM) on the secretion of steroid hormones from the adrenal gland. While some investigators report no effect of this peptide on the output of various hormones, others have reported both stimulatory and inhibitory roles for ADM. We have shown that basal aldosterone secretion rate (ASR), in conscious sheep with cervical adrenal autotransplants, did not change when ADM was infused directly into the adrenal arterial supply. While not affecting basal ASR, ADM did produce pronounced increases in adrenal blood flow (BF). This elevation of BF in association with ADM infusion was seen in all subsequent experiments. When aldosterone output was acutely stimulated by angiotensin II (AngII), potassium chloride (KCl) and adrenocorticotrophic hormone (ACTH), ADM was seen to drastically reduce the secretion of aldosterone with all agonists studied. After pre-exposure to ADM, all three agonists increased ASR but the magnitude of the responses were somewhat blunted. ADM did not have the same effect on cortisol secretion stimulated by ACTH, suggesting that the ability of this peptide to influence adrenal gland function is limited to the zona glomerulosa. In conditions of chronic elevation of aldosterone levels, such as in Na deficiency, ADM did not display the same inhibitory abilities seen in the acute stimulation experiments. Hence, ADM has been shown to have a direct, inhibitory role on the acute stimulation of aldosterone by AngII, KCl and ACTH while not affecting basal or chronic aldosterone secretion or cortisol secretion stimulated by ACTH.
Helge Müller, Juliane Kröger, Olaf Jöhren, Silke Szymczak, Michael Bader, Peter Dominiak, and Walter Raasch
AT1 blockers attenuate hypothalamo-pituitary–adrenal (HPA) axis reactivity in hypertension independently of their potency to lower blood pressure. A reduced pituitary sensitivity to CRH and a downregulation of hypothalamic CRH expression have been suggested to influence HPA axis activity during chronic AT1 blockade. This study was aimed at confirming the role of central angiotensin II in regulating HPA reactivity by using the transgenic rat TGR(ASrAOGEN), a model featuring low levels of brain angiotensinogen. Different stress tests were performed to determine HPA reactivity in TGR(ASrAOGEN) and appropriate controls. In TGR(ASrAOGEN), blood pressure was diminished compared to controls. The corticosterone response to a CRH or ACTH challenge and a forced swim test was more distinct in TGR(ASrAOGEN) than it was in controls and occurred independently of a concurrent enhancement in ACTH. Using quantitative real-time PCR, we found increased mRNA levels of melanocortin 2 (Mc2r) and AT2 receptors (Agtr2) in the adrenals of TGR(ASrAOGEN), whereas mRNA levels of Crh, Pomc, and AT1 receptors (Agtr1) remained unchanged in hypothalami and pituitary glands. Since stress responses were increased rather than attenuated in TGR(ASrAOGEN), we conclude that the reduced HPA reactivity during AT1 blockade could not be mimicked in a specific transgenic rat model featuring a centrally inactivated renin–angiotensin–aldosterone system. The ACTH independency of the enhanced corticosterone release during CRH test and the enhanced corticosterone response to ACTH rather indicates an adrenal mechanism. The upregulation of adrenal MC2 and AT2 receptors seems to be involved in the stimulated facilitation of adrenal corticosterone release for effectuating the stimulated stress responses.
KT Davis, N Prentice, VL Gay, and SA Murray
Mouse and monkey adrenal glands were used to study the relationships between gap junction protein expression, intercellular communication and adrenal zonation. Dye communication patterns were determined by incubating freshly excised and hemisected adrenal glands in Lucifer yellow, a gap junction permeable fluorescent dye. Immunohistochemical techniques were used to localize adrenal gap junction proteins. The combination of these two techniques permitted the correlation of gap junction proteins with dye transfer and hormone responses in specialized regions of the adrenal cortex. Lucifer yellow dye communication was most pronounced in the inner glucocorticoid/androgen-producing regions (zona fasciculata/zona reticularis), but was virtually absent in the outer mainly mineralocorticoid-producing region (zona glomerulosa). This pattern of dye communication was coincident with immunohistochemical localization of the gap junction protein, alpha(1)Cx43. The variations in communication and alpha(1)Cx43 expression within the adrenal cortex are thought to be relevant to normal physiological regulation of the adrenal gland.
Duarte Pignatelli, Fang Xiao, Alexandra M Gouveia, Jorge G Ferreira, and Gavin P Vinson
Normal pubertal development in humans involves two distinct processes: maturation of adrenal androgen secretion (adrenarche) and activation of the hypothalamic–pituitary–gonadal axis (gonadarche). One factor thought to contribute to the adrenarche in man is increased adrenal 17-hydroxylase (CYP17) activity. In the rat, there is evidence for adrenal involvement in the initiation of puberty, but the adrenal glands of this species are generally thought to express CYP17 only very poorly at best. To further examine the nature of postnatal adrenal development in rat, plasma samples and adrenal tissues were taken from animals aged 2–90 days, circulating adrenal steroids assayed, and adrenal zones assessed quantitatively. A relative increase in zona reticularis, and peaks of circulating cortisol, androstenedione, and 17-OH-progesterone were observed around postnatal days 16–20, clearly before the development of the gonads, which begins at 30–35 days. Quantitative reverse transcriptase PCR confirmed a peak in mRNA coding for CYP17 in adrenal tissue from rats of similar age. The results suggest that the rat adrenal has the capacity to secrete steroids arising from 17-hydroxylation, and that this may contribute to a process similar to human adrenarche.