The angiotensin type 2 receptor in the human adrenocortical zona glomerulosa and in aldosterone-producing adenoma: low expression and no functional role

Vanderriele, Paul-Emmanuel; Caroccia, Brasilina; Seccia, Teresa Maria; Piazza, Maria; Lenzini, Livia; Torresan, Francesca; Iacobone, Maurizio; Unger, Thomas; Rossi, Gian Paolo

doi:10.1042/cs20171593

Cited by 17 publications

(12 citation statements)

References 44 publications

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“…We used human adrenocortical tissues, which were obtained ex vivo with utmost care to avoid peptide degradation, to investigate the tissue amounts of Ang II. In keeping with results of functional studies [27][28][29][30], and with the detection of renin [8] and the AT-1R in such tumours [9], we detected Ang II also in some APA and APA-adjacent tissues suggesting that the peptide can play a role in human PA. Interestingly, we did find detectable amounts of both Ang I and Ang II in blood draining from the human adrenal glands of primary aldosteronism patients (Table 1), at similar levels from the adrenal gland harbouring the APA and causing primary aldosteronism, and from the 'nonculprit' adrenal gland. These findings can challenge the view that APAs, or at least a subset of them, are autonomous from Ang II.…”

Section: Discussionsupporting

confidence: 90%

Aldosterone and cortisol synthesis regulation by angiotensin-(1-7) and angiotensin-converting enzyme 2 in the human adrenal cortex

Caroccia

Vanderriele

Seccia

et al. 2021

Journal of Hypertension

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The branch of the renin-angiotensin system constituting angiotensin-(1-7) [Ang-(1-7)], the Ang II type 2 receptor, the Mas receptors and the Ang-(1-7)-forming enzyme ACE-2, by counteracting the Ang II type 1 receptor (AT1R)-mediated effects, are held to be cardiovascular protective in several conditions. However, whether Ang-(1-7) and ACE-2 are detectable in human adrenocortical tissues and whether they affect aldosterone and cortisol biosynthesis was unknown. Methods:We measured angiotensin peptides with liquid chromatography tandem-mass spectrometry and ACE-2 mRNA with digital droplet (dd)PCR in human aldosteroneproducing adenoma (APA) and APA-adjacent tissue obtained from patients with primary aldosteronism. We also investigated the effects of Ang-(1-7) and the ACE-2 activator diminazene aceturate (DIZE) on aldosterone synthase (CYP11B2) and 11b-hydroxylase (CYP11B1) gene expression, in the absence or presence of the AT1R antagonist irbesartan, or of the MasR antagonist A779.Results: APA and APA-adjacent adrenocortical tissues express ACE-2 mRNA and contain detectable amounts of Ang II and Ang-(2-8), but not of Ang I, Ang-(1-5), Ang (3-8) and Ang-(1-7). Under unstimulated and Ang IIstimulated conditions Ang-(1-7) did not blunt CYP11B1 and CYP11B2 mRNA. At supraphysiological concentrations (10 À4 mol/l), Ang-(1-7) stimulated both CYP11B1 and CYP11B2 mRNA via the AT1R. The ACE-2 activator DIZE increased by 1.5-fold ACE-2 mRNA but did not blunt Ang II-upregulated CYP11B1 and CYP11B2 expression. Conclusion:These results do not support the hypothesis that the ACE-2/Ang-(1-7)/MasR axis play a protective role by counteracting enhanced aldosterone secretion in humans.

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Section: Discussionsupporting

confidence: 90%

Aldosterone and cortisol synthesis regulation by angiotensin-(1-7) and angiotensin-converting enzyme 2 in the human adrenal cortex

Caroccia

Vanderriele

Seccia

et al. 2021

Journal of Hypertension

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“…As proof-of-concept that Ang II can regulate cortisol production, we provided in vivo evidences for a stimulatory effect of Ang II by treating rats with Ang II (700 μg/kg•day) for 1-week and demonstrating an increase of immunodetectable 11-β hydroxylase in the adrenal cortex (Figure 3) [38]. Furthermore, by acting on AT1R, Ang II, significantly increased CYP11B1 gene expression in adrenocortical cell line H295R and its sub-clone HAC15, and also in strips obtained from APA-adjacent tissue and APA [11,28].…”

Section: Angiotensin Peptides and Cortisol And Androgen Biosynthesismentioning

confidence: 86%

“…Of note, at high concentration (10 -5 M) C21 markedly increased CYP11B2 gene expression and enhanced the effect of Ang II on expression of this gene. This effect was abolished by pre-treatment with the AT1R antagonist irbesartan, indicating that at high concentration (10 -5 M) C21 acts as an AT1R agonist [28].…”

Section: Ang II and Angiotensin Receptors In The Regulation Of Aldosterone Productionmentioning

confidence: 96%

“…Considering that the AT2R is expressed in the adrenal gland, we explored its role in aldosterone secretion with a pharmacological approach using the AT2R agonist C21 [28] to determine if activation of the AT2R could counter-regulate the AT1R-mediated secretagogue effect of Ang II. These experiments showed that AT2R activation with C21 had no effect on aldosterone production in human adrenocortical cells under unstimulated conditions and also when aldosterone secretion was up-regulated by Ang II [29].…”

Section: Ang II and Angiotensin Receptors In The Regulation Of Aldosterone Productionmentioning

confidence: 99%

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Angiotensin peptides in the regulation of adrenal cortical function

Rossi¹,

Lenzini

Caroccia

et al. 2021

Exploration of Medicine

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The adrenal cortex plays a key role in the regulation of metabolism, salt and water homeostasis and sex differentiation by synthesizing glucocorticoid, mineralocorticoid and androgen hormones. Evidence exists that angiotensin II regulates adrenocortical function and it has been contended that angiotensin peptides of the non-canonical branch of the renin angiotensin system (RAS) might also modulate steroidogenesis in adrenals. Thus, the aim of this review is to examine the role of the RAS, and particularly of the angiotensin peptides and their receptors, in the regulation of adrenocortical hormones with particular focus on aldosterone production.

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“…Aldosterone biosynthesis is under the control of potassium and angiotensin II, which increase the levels of CYP 11B2 mRNA and lead to an increase in the activity of aldosterone synthase [ 54 , 55 , 56 , 57 , 58 ]. High potassium diets in rats increase the expression of CYP11B2 in the adrenal gland and aldosterone production [ 59 ].…”

Section: Contribution Of Dna Methylation To Human Cyp11b2 Transcriptionmentioning

confidence: 99%

DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

Takeda

Demura

Yoneda

et al. 2021

IJMS

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Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene CYP11B2 is regulated by angiotensin II and potassium. DNA methylation negatively regulates AGT and CYP11B2 expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the CYP11B2 promoter region, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac AGT expression. CpG dinucleotides in the CYP11B2 promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated CYP11B2 promoter. Low salt intake and angiotensin II infusion lead to upregulation of CYP11B2 expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases CYP11B2 expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased CYP11B2 expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both AGT and CYP11B2 contribute to the pathogenesis of cardiovascular diseases.

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The angiotensin type 2 receptor in the human adrenocortical zona glomerulosa and in aldosterone-producing adenoma: low expression and no functional role

Cited by 17 publications

References 44 publications

Aldosterone and cortisol synthesis regulation by angiotensin-(1-7) and angiotensin-converting enzyme 2 in the human adrenal cortex

Aldosterone and cortisol synthesis regulation by angiotensin-(1-7) and angiotensin-converting enzyme 2 in the human adrenal cortex

Angiotensin peptides in the regulation of adrenal cortical function

DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

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