ALDOSTERONE INDUCES CYP11B2 GENE EXPRESSION VIA GPER-1 ACTIVATION IN HUMAN ADRENOCORTICAL CELL (HAC15) AND STRIPS FROM ALDOSTERONE PRODUCING ADENOMA

Context: Primary aldosteronism (PAL) is the most frequent cause of secondary arterial hypertension. In PAL, aldosterone production is chronic, excessive, and autonomous. Objective: The objective of this study was to identify the angiotensin-II independent alterations of steroidogenesis responsible for PAL. Design: Genomewide gene expression was compared in two tissues differentiated for aldosterone production, both nonstimulated by circulating angiotensin II and differing in their autonomy to produce aldosterone: aldosterone-producing adenoma (APA) and its adjacent dissected zona glomerulosa (ZG). Setting: The setting of this study was the Comete Network. Patients: Patients with APA were studied. Intervention: Transcriptome comparison was made of one APA and its adjacent ZG by serial analysis of gene expression; validation by in situ hybridization was performed for 19 genes in 11 samples. Outcome: The study outcome was genes differentially expressed in APA and adjacent ZG. Results: Activation of steroidogenesis in PAL is restricted to the overexpression of the enzymes producing aldosterone-specific steroids, aldosterone synthase and also 21-hydroxylase, suggesting that upstream precursor production is not limiting. Increased expression of high-density lipoprotein receptor, adrenodoxin and P450 oxidoreductase suggests that these systems provide cholesterol and electrons to the mitochondrial steroidogenic enzymes. As for acute stimulation of aldosterone production, an activation of calcium signaling is suggested by concordant overexpression of calcium-binding proteins or effectors. Calcium activation may result from an abnormal activity of Gq protein-coupled receptors. This calcium activation may be the starting point of the other gene expression changes observed in APA. Finally, other differentially expressed genes include three genes encoding unidentified proteins. Conclusion: This work provides an original and integrated view of the mechanisms of aldosterone production in PAL.

Download Full-text

In Silico Analysis of the Gene Expression Patterns between Aldosterone-Producing Adenoma and Nonfunctional Adrenocortical Adenoma

Genetics Research ◽

10.1155/2021/9553637 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Yongfa Dai ◽

Jing Li ◽

Hong Wen ◽

Jie Liu ◽

Jianling Li

Keyword(s):

Gene Expression ◽

Expression Pattern ◽

Primary Aldosteronism ◽

Expression Patterns ◽

Gene Expression Pattern ◽

Gene Expression Patterns ◽

Pathophysiological Mechanism ◽

Adrenocortical Adenoma ◽

Hub Genes ◽

Aldosterone Producing Adenoma

Primary aldosteronism is the most common form of secondary hypertension, and aldosteronoma makes up a significant proportion of primary aldosteronism cases. Aldosteronoma is also called aldosterone-producing adenoma (APA). Although there have been many studies about APA, the pathogenesis of this disease is not yet fully understood. In this study, we aimed to find out the difference of gene expression patterns between APA and nonfunctional adrenocortical adenoma (NFAA) using a weighted gene coexpression network (WGCNA) and differentially expressed gene (DEG) analysis; only the genes that meet the corresponding standards of both methods were defined as real hub genes and then used for further analysis. Twenty-nine real hub genes were found out, most of which were enriched in the phospholipid metabolic process. WISP2, S100A10, SSTR5-AS1, SLC29A1, APOC1, and SLITRK4 are six real hub genes with the same gene expression pattern between the combined and validation datasets, three of which indirectly or directly participate in lipid metabolism including WISP2, S100A10, and APOC1. According to the gene expression pattern of DEGs, we speculated five candidate drugs with potential therapeutic value for APA, one of which is cycloheximide, an inhibitor for phospholipid biosynthesis. All the evidence suggests that phospholipid metabolism may be an important pathophysiological mechanism for APA. Our study provides a new perspective regarding the pathophysiological mechanism of APA and offers some small molecules that may possibly be effective drugs against APA.

Download Full-text

Adrenal Corticosteroid Perturbation by the Endocrine Disruptor BDE-47 in a Human Adrenocortical Cell Line and Male Rats

Endocrinology ◽

10.1210/endocr/bqab160 ◽

2021 ◽

Author(s):

Benjamin M Dungar ◽

Chad D Schupbach ◽

Jessie R Jacobson ◽

Phillip G Kopf

Keyword(s):

Gene Expression ◽

Cell Line ◽

Polybrominated Diphenyl Ethers ◽

Plasma Corticosterone ◽

Male Rats ◽

Cortisol Secretion ◽

Adrenocortical Cell ◽

Sprague Dawley ◽

Treatment Groups ◽

Corticosteroid Secretion

Abstract Polybrominated diphenyl ethers (PBDEs) have been previously shown to alter various endocrine biosynthetic pathways. Growing epidemiological evidence suggests that PBDEs alter cardiovascular function. The goal of this study was to examine the effects of BDE-47 on adrenal corticosteroid pathways that play vital roles in cardiovascular homeostasis and pathophysiology. The effect of BDE-47 on aldosterone and cortisol secretion was characterized in a human adrenocortical cell line. HAC15 cells were exposed to various concentrations of BDE-47 (1 nM-100 μM). Cell viability, corticosteroid secretion, gene expression of enzymes involved in corticosteroid synthesis, and metabolic activity was examined. Additionally, Sprague Dawley male rats were orally exposed to BDE-47 (10 or 100 µg/kg), 5 days per week for 16 weeks. Organ weights and plasma corticosteroid levels were measured. In HAC15 cells, basal and stimulated aldosterone and cortisol secretion was significantly increased by BDE-47. Gene expression of several enzymes involved in corticosteroid synthesis and mitochondrial metabolism were also increased. In Sprague Dawley rats, adrenal, but not heart, kidney, or liver weights, were significantly increased in BDE-47 treatment groups. Plasma corticosterone levels were significantly increased in the 100 µg BDE-47/kg treatment group. No change in plasma aldosterone levels were observed with BDE-47 exposure. These data indicate that BDE-47 disrupts the regulation of corticosteroid secretion and provides further evidence that PBDEs are potential endocrine disruptors. Future studies will determine the underlying molecular mechanism of altered corticosteroid production and examine whether these alterations result in underlying cardiovascular disease in our rodent model of 16 week BDE-47 exposure.

Download Full-text

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

Clinical Science ◽

10.1042/cs20171593 ◽

2018 ◽

Vol 132 (6) ◽

pp. 627-640 ◽

Cited By ~ 4

Author(s):

Paul-Emmanuel Vanderriele ◽

Brasilina Caroccia ◽

Teresa Maria Seccia ◽

Maria Piazza ◽

Livia Lenzini ◽

...

Keyword(s):

Gene Expression ◽

Cell Lines ◽

Hormone Secretion ◽

Zona Glomerulosa ◽

Ang Ii ◽

Aldosterone Synthase ◽

Adjacent Tissue ◽

Angiotensin Type 2 Receptor ◽

Aldosterone Producing Adenoma

The angiotensin II (Ang II) type 2 receptor (AT2R) and the angiotensin-(1–7) (Ang-(1–7)) receptor (MasR) play a cardiovascular protective role by counter-regulating Ang II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R, and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of Compound 21 (C21), an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin–angiotensin system (RAS) blunts aldosterone synthase in the normal adrenal cortex and primary aldosteronism.

Download Full-text