scholarly journals Regulation of aldosterone production by ion channels: From basal secretion to primary aldosteronism

2018 ◽  
Vol 1864 (3) ◽  
pp. 871-881 ◽  
Author(s):  
Tingting Yang ◽  
Min He ◽  
Changlong Hu
Keyword(s):  
Ion Channels ◽  
Primary Aldosteronism ◽  
Basal Secretion ◽  
Aldosterone Production

Characterization of a mutated KCNJ5 gene, G387R, in unilateral primary aldosteronism

2021 ◽  
Vol 67 (4) ◽  
pp. 203-215
Author(s):  
Jeff S Chueh ◽  
Kang-Yung Peng ◽  
Vin-Cent Wu ◽  
Shuo-Meng Wang ◽  
Chieh-Kai Chan ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Bioinformatics Analysis ◽  
Genomic Analysis ◽  
Ion Current ◽  
Mutant Channel ◽  
Transfected Cells ◽  
Aldosterone Production ◽  
Mutant Cells ◽  
Electrophysiological Experiment

Somatic mutation in the KCNJ5 gene is a common driver of autonomous aldosterone overproduction in aldosterone-producing adenomas (APA). KCNJ5 mutations contribute to a loss of potassium selectivity, and an inward Na+ current could be detected in cells transfected with mutated KCNJ5. Among 223 unilateral primary aldosteronism (uPA) individuals with a KCNJ5 mutation, we identified 6 adenomas with a KCNJ5 p.Gly387Arg (G387R) mutation, previously unreported in uPA patients. The six uPA patients harboring mutant KCNJ5-G387R were older, had a longer hypertensive history, and had milder elevated preoperative plasma aldosterone levels than those APA patients with more frequently detected KCNJ5 mutations. CYP11B2 immunohistochemical staining was only positive in three adenomas, while the other three had co-existing multiple aldosterone-producing micronodules. The bioinformatics analysis predicted that function of the KCNJ5-G387R mutant channel could be pathological. However, the electrophysiological experiment demonstrated that transfected G387R mutant cells did not have an aberrantly stimulated ion current, with lower CYP11B2 synthesis and aldosterone production, when compared to that of the more frequently detected mutant KCNJ5-L168R transfected cells. In conclusion, mutant KCNJ5-G387R is not a functional KCNJ5 mutation in unilateral PA. Compared with other KCNJ5 mutations, the observed mildly elevated aldosterone expression actually hindered the clinical identification of clinical unilateral PA. The KCNJ5-G387R mutation needs to be distinguished from functional KCNJ5 mutations during genomic analysis in APA evaluation because of its functional silence.

scholarly journals Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ute I Scholl ◽  
Gabriel Stölting ◽  
Carol Nelson-Williams ◽  
Alfred A Vichot ◽  
Murim Choi ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Early Onset ◽  
De Novo ◽  
Incomplete Penetrance ◽  
De Novo Mutations ◽  
Channel Inactivation ◽  
Aldosterone Production ◽  
Genome Level ◽  
Insight Into

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

Local Control of Aldosterone Production and Primary Aldosteronism

2016 ◽  
Vol 27 (3) ◽  
pp. 123-131 ◽  
Author(s):  
Enzo Lalli ◽  
Jacques Barhanin ◽  
Maria-Christina Zennaro ◽  
Richard Warth
Keyword(s):  
Local Control ◽  
Primary Aldosteronism ◽  
Aldosterone Production

scholarly journals CACNA1HM1549V Mutant Calcium Channel Causes Autonomous Aldosterone Production in HAC15 Cells and Is Inhibited by Mibefradil

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3016-3022 ◽  
Author(s):  
Esther N. Reimer ◽  
Gudrun Walenda ◽  
Eric Seidel ◽  
Ute I. Scholl
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Cancer Cell Line ◽  
Fold Increase ◽  
Extracellular Potassium ◽  
Channel Blockers ◽  
Adrenocortical Cancer ◽  
Transfected Cells ◽  
Channel Inactivation ◽  
Aldosterone Production

We recently demonstrated that a recurrent gain-of-function mutation in a T-type calcium channel, CACNA1HM1549V, causes a novel Mendelian disorder featuring early-onset primary aldosteronism and hypertension. This variant was found independently in five families. CACNA1HM1549V leads to impaired channel inactivation and activation at more hyperpolarized potentials, inferred to cause increased calcium entry. We here aimed to study the effect of this variant on aldosterone production. We heterologously expressed empty vector, CACNA1HWT and CACNA1HM1549V in the aldosterone-producing adrenocortical cancer cell line H295R and its subclone HAC15. Transfection rates, expression levels, and subcellular distribution of the channel were similar between CACNA1HWT and CACNA1HM1549V. We measured aldosterone production by an ELISA and CYP11B2 (aldosterone synthase) expression by real-time PCR. In unstimulated cells, transfection of CACNA1HWT led to a 2-fold increase in aldosterone levels compared with vector-transfected cells. Expression of CACNA1HM1549V caused a 7-fold increase in aldosterone levels. Treatment with angiotensin II or increased extracellular potassium levels further stimulated aldosterone production in both CACNA1HWT- and CACNA1HM1549V-transfected cells. Similar results were obtained for CYP11B2 expression. Inhibition of CACNA1H channels with the T-type calcium channel blocker Mibefradil completely abrogated the effects of CACNA1HWT and CACNA1HM1549V on CYP11B2 expression. These results directly link CACNA1HM1549V to increased aldosterone production. They suggest that calcium channel blockers may be beneficial in the treatment of a subset of patients with primary aldosteronism. Such blockers could target CACNA1H or both CACNA1H and the L-type calcium channel CACNA1D that is also expressed in the adrenal gland and mutated in patients with primary aldosteronism.

Identification of aldosterone production sites in primary aldosteronism

Pathology ◽  
2014 ◽  
Vol 46 ◽  
pp. S14
Author(s):  
Hironobu Sasano ◽  
Yasuhiro Nakamura ◽  
Fumitoshi Satoh
Keyword(s):  
Primary Aldosteronism ◽  
Aldosterone Production

Success of Surgery for Primary Aldosteronism Judged by Residual Autonomous Aldosterone Production

1998 ◽  
Vol 22 (12) ◽  
pp. 1243-1245 ◽  
Author(s):  
John C. Rutherford ◽  
Wendy L. Taylor ◽  
Michael Stowasser ◽  
Richard D. Gordon
Keyword(s):  
Primary Aldosteronism ◽  
Aldosterone Production

scholarly journals MON-LB129 A Pilot Genome Wide Association Study (GWAS) on Primary Aldosteronism Patients in a Multi-Ethnic Malaysian Cohort

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Elena AB Azizan ◽  
Mohammad Arif Shahar ◽  
Siti Liyana Saud Ghany ◽  
A Rahman A Jamal ◽  
Nor Azmi Kamaruddin ◽  
...  
Keyword(s):  
Association Study ◽  
Primary Aldosteronism ◽  
Genome Wide Association Study ◽  
Spontaneously Hypertensive Rat ◽  
Nuclear Hormone Receptor ◽  
Orphan Receptor ◽  
Genome Wide Association ◽  
P Value ◽  
Genome Wide ◽  
Aldosterone Production

Abstract Studies on excised aldosterone-producing lesions have found somatic mutations in five genes (KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1) commonly causes the excess aldosterone production. Interestingly, Oriental cohorts had the highest frequency of KCNJ5 mutations whereas CACNA1D mutations were most common in Black African Caribbean patients, suggesting that genetic background affects the prevalence and distribution of aldosterone-driving somatic mutation. We therefore aimed to identify the common germline variants that associates with excess aldosterone production through performing a pilot genome wide association study (GWAS) on primary aldosteronism (PA) patients. GWAS was performed using the Human Infinium OmniExpressExome-8 v1.4 BeadChip containing 960,919 markers to compare gDNA of 154 PA patients with 78 healthy controls. Samples were checked for sex discordance, heterozygosity rate, missing rate and the degree of recent shared ancestry for each pair of individuals using the PLINK program and Genome Studio (Illumina). In total, 150 patients and 75 controls (112 males and 113 females) were included in the downstream analysis. 630,749 markers that passed quality control steps (missing call rate <95% and minor allele frequency in controls >1%) were used to perform association analysis using the Chi-square Test which was then subjected to multiple testing corrections (Bonferroni correction). As expected with a pilot sample size, no variants passed the suggestive significant threshold of Bonferroni corrected P-value < 5 x 10-6 (-log10 P = 5.3). However, 27 SNPs had the uncorrected P-value<0.0002, odds ratio >2, and differences of frequencies in cases compared to control >0.1 or <-0.2, of which 3 genes (SRGAP3, AUTS2, and RORA) associated with these SNPs were also highlighted in the UK Biobank database of 72 patients with primary aldosteronism (https://biobankengine.stanford. edu/coding/HC189). Of these, RORA has recently been found to be down-regulated in adrenals from PA patients and spontaneously hypertensive rat adrenals compared to control adrenalsa,b. RORA encodes for the protein retinoic acid receptor (RAR)-related orphan receptor alpha, a member of the NR1 subfamily of nuclear hormone receptors (NR1F1). Interestingly, adrenal is the second organ to skin with the highest expression of RORA and treatment of angiotensin II in the adrenocortical cell line H295R increases RORA expressionc,d. Taken together, this pilot GWAS highlights RORA as a potential nuclear hormone receptor that regulates aldosterone production. References aChu et al., Int J Clin Exp Pathol 2017;10(9):10009-10018. bTanaka et al., Hypertens Res 2019;42(2):165-173. cNogueira et al., Mol Cell Endocrinol 2009; 302(2): 230–236. dGTEx Analysis Release V7 (dbGaP Accession phs000424.v7.p2) Acknowledgements This research was supported by the Malaysian Ministry of Higher Education Grant (FRGS/1/2015/SKK08/UKM/02/3), The National University of Malaysia (UKM) University Grant (GUP-2016-083), and The UKM Medical Center Fundamental Grant (FF-2016-302).

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: The role of confirmatory tests in the diagnosis of primary aldosteronism

2019 ◽  
Vol 180 (2) ◽  
pp. R45-R58 ◽  
Author(s):  
Julia Morera ◽  
Yves Reznik
Keyword(s):  
Primary Aldosteronism ◽  
Dynamic Testing ◽  
High Sensitivity ◽  
Plasma Aldosterone ◽  
Plasma Aldosterone Concentration ◽  
Aldosterone Production ◽  
Confirmatory Tests ◽  
Aldosterone To Renin Ratio ◽  
Work Up

The strategy for diagnosis of primary aldosteronism (PA) in the hypertensive population includes firstly a screening step, based on the measurement of plasma aldosterone-to-renin ratio (ARR), a test which must have high sensitivity, and secondly a confirmatory step based on the demonstration of excessive aldosterone production independent of the renin-angiotensin-aldosterone system (RAAS) activity. The high proportion of false-positive ARR results and conversely of actual PA without a persistent elevation in baseline plasma aldosterone concentration necessitates the addition of a confirmatory step in the work-up of PA diagnosis. The present review focuses on the description of the different dynamic tests available for demonstrating autonomy of aldosterone secretion, on the performance and limitations of confirmatory tests and on possible strategies for PA diagnosis which may either include or avoid the confirmatory step for PA diagnosis. Large prospective studies comparing different strategies with and without dynamic testing are mandatory to delineate clearly the role and limits of confirmatory tests in the work-up of PA.

scholarly journals Modulation of Calcium Signaling by Chemogenetic Tools to Elucidate the Pathogenesis of Primary Aldosteronism

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A294-A295
Author(s):  
Teresa Cosentino ◽  
Bakhta Fedlaoui ◽  
Isabelle Giscos-Douriez ◽  
Fabio Luiz Fernandes-Rosa ◽  
Christopher Magnus ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ion Channels ◽  
Ligand Binding ◽  
Calcium Signaling ◽  
Intracellular Calcium ◽  
Acetylcholine Receptor ◽  
Cell Lines ◽  
Primary Aldosteronism ◽  
Calcium Entry ◽  
Steroidogenic Genes

Abstract Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. The identification of germline or somatic mutations in different genes coding for ion channels (KCNJ5, CACNA1D, CACNA1H and CLCN2) and ATPases (ATP1A1 and ATP2B3) defines PA as a channelopathy. These mutations promote increased intracellular calcium concentrations and activation of calcium signaling, the main trigger for aldosterone biosynthesis. The aim of our study was to elucidate the mechanisms underlying the development of PA by modulating calcium signaling using chemogenetic tools. We have generated two different adrenocortical H295R_S2 cell lines stably expressing different chimeric ion channels generated by fusing the mutated extracellular ligand binding domain of the α7 nicotinic acetylcholine receptor to the ion pore domain of large Cys-loop receptor ion channel family; these receptors constitute PSAM (Pharmacologically Selective Actuator Modules). The mutations introduced in the ligand-binding domain allow to use synthetic ligands, PSEM (Pharmacologically Selective Effector Molecules) to activate the PSAM. We used two different PSAM: the chimeric receptor α7-5HT3 or a mutated acetylcholine receptor nAchR, allowing respectively modulation of sodium or calcium entry into the cells in response to the specific PSEM: Varenicline for α7-5HT3 or Compound 9S for mutated nAChR. The cells lines were characterized in terms of intracellular calcium concentrations, cell proliferation, aldosterone production and steroidogenic gene expression. Cells expressing α7-5HT3 treated for 24h with increasing concentrations of Varenicline (10–9 to 10-5M) showed increased intracellular calcium concentrations and an increase in expression of steroidogenic genes such as StAR CYP17A1, CYP21A2 and CYP11B2. Cell proliferation was not affected. Calcium entry into cells expressing the mutated nAChR receptor treated for 24h with increasing concentrations of Compound 9S (10–9 to 10-5M) induced an increase in expression of steroidogenic genes such as StAR, CYP21A2 and HSD3B2, but not CYP11B2. Similarly to the results obtained in cells expressing α7-5HT3, cell proliferation was unaffected in response to Compound 9S. These cell lines, in which we can modulate the intracellular calcium concentration « on demand », are a useful tool for a better understanding of the alterations of intracellular ion balance and calcium signaling in the pathophysiology of PA.

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