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Article: Aldosterone and Ion Channels.

Valinsky, William C / Touyz, Rhian M / Shrier, Alvin

2018 Volume 109, Page(s) 105–131

Abstract: Since its discovery, aldosterone and ion modulation have been entwined. While scientific ... investigations throughout the decades have emphasized aldosterone's connection to Na ...

Abstract	Since its discovery, aldosterone and ion modulation have been entwined. While scientific investigations throughout the decades have emphasized aldosterone's connection to Na
MeSH term(s)	Aldosterone/metabolism ; Animals ; Gene Expression Regulation/physiology ; Genomics ; Ion Channels/genetics ; Ion Channels/metabolism
Chemical Substances	Ion Channels ; Aldosterone (4964P6T9RB)
Language	English
Publishing date	2018-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/bs.vh.2018.10.004
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Article ; Online: Aldosterone, SGK1, and ion channels in the kidney.

Valinsky, William C / Touyz, Rhian M / Shrier, Alvin

Clinical science (London, England : 1979)

2018 Volume 132, Issue 2, Page(s) 173–183

Abstract: Hyperaldosteronism, a common cause of hypertension, is strongly connected to ... ...

Abstract	Hyperaldosteronism, a common cause of hypertension, is strongly connected to Na
MeSH term(s)	Aldosterone/metabolism ; Animals ; Humans ; Immediate-Early Proteins/metabolism ; Ion Channels/metabolism ; Kidney/metabolism ; Nephrons/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction ; Up-Regulation
Chemical Substances	Immediate-Early Proteins ; Ion Channels ; Aldosterone (4964P6T9RB) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; serum-glucocorticoid regulated kinase (EC 2.7.11.1)
Language	English
Publishing date	2018-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20171525
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Article ; Conference proceedings: Meeting program and abstracts / 7th International Symposium on Aldosterone and the ENaC/Degenerin Family of Ion Channels

American Physiological Society

The physiologist 54 ,6, S. 1 - 31

molecular mechanisms and pathophysiology ; 2011 American Physiological Society conference ; Pacific Grove, California, September 18 - 22, 2011

2011

Title variant	Aldosterone and the ENaC/Degenerin family of ion channels
Event/congress	International Symposium on Aldosterone and the ENaC/Degenerin Family of Ion Channels (7, 2011, PacificGroveCalif.)
Collection	The physiologist
Language	English
Publishing place	Bethesda, Md.
Publishing country	United States
Document type	Article ; Conference proceedings
HBZ-ID	HT017283916
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Article ; Online: Behavior of the renal kallikrein in spontaneously hypertensive rats: Influence of sexual hormones and aldosterone-sensitive distal nephron ion channels.

Azurmendi, Pablo Javier / Toro, Ayelén Rayen / Celía, Alejandro Fabián / Guevara, Darío / Solerno, Martín Rogelio / Di Ciano, Luis Alberto / Toledo, Jorge Eduardo / Ibarra, Fernando Raúl / Arrizurieta, Elvira Emilia / Oddo, Elisabet Mónica

Peptides

2022 Volume 160, Page(s) 170925

Abstract: The renal kallikrein-kinin system (RKKS) has been related to blood pressure control and sodium and ... kallikrein activity (UKa) and lower blood pressure (BP) than males whereas ovariectomy stimulates UKa and ...

Abstract	The renal kallikrein-kinin system (RKKS) has been related to blood pressure control and sodium and water balance. We have previously shown that female spontaneously hypertensive rats (SHR) have high urinary kallikrein activity (UKa) and lower blood pressure (BP) than males whereas ovariectomy stimulates UKa and diminishes BP. We also showed that high K
MeSH term(s)	Male ; Rats ; Female ; Animals ; Aldosterone/metabolism ; Rats, Inbred SHR ; Receptors, Mineralocorticoid/metabolism ; Hypertension/metabolism ; Kallikreins/genetics ; Kallikreins/metabolism ; Kidney/metabolism ; Nephrons/metabolism ; Sodium/metabolism ; Ion Channels/metabolism ; Epithelial Sodium Channels/genetics ; Epithelial Sodium Channels/metabolism
Chemical Substances	Aldosterone (4964P6T9RB) ; Receptors, Mineralocorticoid ; Kallikreins (EC 3.4.21.-) ; Sodium (9NEZ333N27) ; Ion Channels ; Epithelial Sodium Channels
Language	English
Publishing date	2022-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	769028-9
ISSN	1873-5169 ; 0196-9781
ISSN (online)	1873-5169
ISSN	0196-9781
DOI	10.1016/j.peptides.2022.170925
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Article ; Online: Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production.

Wu, Xilin / Azizan, Elena A B / Goodchild, Emily / Garg, Sumedha / Hagiyama, Man / Cabrera, Claudia P / Fernandes-Rosa, Fabio L / Boulkroun, Sheerazed / Kuan, Jyn Ling / Tiang, Zenia / David, Alessia / Murakami, Masanori / Mein, Charles A / Wozniak, Eva / Zhao, Wanfeng / Marker, Alison / Buss, Folma / Saleeb, Rebecca S / Salsbury, Jackie /

Nature genetics

2023 Volume 55, Issue 6, Page(s) 1009–1021

Abstract: ... gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery ... whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more ... Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have ...

Abstract	Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.
MeSH term(s)	Humans ; Aldosterone ; Cytochrome P-450 CYP11B2 ; Adrenocortical Adenoma ; Gap Junctions ; Hypertension ; Mutation ; Hyperaldosteronism ; Adrenal Cortex Neoplasms ; Cell Adhesion Molecule-1
Chemical Substances	Aldosterone (4964P6T9RB) ; Cytochrome P-450 CYP11B2 (EC 1.14.15.4) ; CADM1 protein, human ; Cell Adhesion Molecule-1
Language	English
Publishing date	2023-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01403-0
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Article ; Online: TSPAN12 (Tetraspanin 12) Is a Novel Negative Regulator of Aldosterone Production in Adrenal Physiology and Aldosterone-Producing Adenomas.

Gong, Siyuan / Tetti, Martina / Kemter, Elisabeth / Peitzsch, Mirko / Mulatero, Paolo / Bidlingmaier, Martin / Eisenhofer, Graeme / Wolf, Eckhard / Reincke, Martin / Williams, Tracy Ann

Hypertension (Dallas, Tex. : 1979)

2022 Volume 80, Issue 2, Page(s) 440–450

Abstract: ... production and could contribute to aldosterone overproduction in primary aldosteronism. ... activating mutation in an ion pump or channel. : Methods: APA specimens, pig adrenals under dietary sodium ... Background: Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism ...

Abstract	Background: Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism, a condition of low-renin hypertension, in which aldosterone overproduction is usually driven by a somatic activating mutation in an ion pump or channel. Methods: APA specimens, pig adrenals under dietary sodium modulation, and a human adrenocortical cell line HAC15 were used for functional characterization of TSPAN12 in vivo and in vitro. Results: Gene ontology analysis of 21 APA transcriptomes dichotomized according to high versus low Conclusions: Our findings show that TSPAN12 is a negative regulator of aldosterone production and could contribute to aldosterone overproduction in primary aldosteronism.
MeSH term(s)	Humans ; Animals ; Swine ; Aldosterone/metabolism ; Angiotensin II/pharmacology ; Hyperaldosteronism/metabolism ; Adrenocortical Adenoma/metabolism ; Adrenal Cortex Neoplasms/metabolism ; Adenoma/metabolism ; Tetraspanins/genetics
Chemical Substances	Aldosterone (4964P6T9RB) ; Angiotensin II (11128-99-7) ; Tetraspanins ; TSPAN12 protein, human
Language	English
Publishing date	2022-12-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.122.19783
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Article ; Online: Update on the Genetics of Primary Aldosteronism and Aldosterone-Producing Adenomas.

Pitsava, Georgia / Faucz, Fabio R / Stratakis, Constantine A / Hannah-Shmouni, Fady

Current cardiology reports

2022 Volume 24, Issue 9, Page(s) 1189–1195

Abstract: ... from bilateral adrenocortical hyperplasia (BAH) and aldosterone-producing adenoma (APA). We discuss recent ... depolarization, and consequently aldosterone overproduction. Some of these genes are found ... encode ion channels; pathogenic variants found in PA lead to altered ion transportation, cell membrane ...

Abstract	Purpose of the review: Primary aldosteronism (PA) is the leading cause of secondary hypertension, accounting for over 10% of patients with high blood pressure. It is characterized by autonomous production of aldosterone from the adrenal glands leading to low-renin levels. The two most common forms arise from bilateral adrenocortical hyperplasia (BAH) and aldosterone-producing adenoma (APA). We discuss recent discoveries in the genetics of PA. Recent findings: Most APAs harbor variants in the KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 genes. With the exception of β-catenin (CTNNB1), all other causative genes encode ion channels; pathogenic variants found in PA lead to altered ion transportation, cell membrane depolarization, and consequently aldosterone overproduction. Some of these genes are found mutated in the germline state (CYP11B2, CLCN2, KCNJ5, CACNA1H, and CACNA1D), leading then to familial hyperaldosteronism, and often BAH rather than single APAs. Several genetic defects in the germline or somatic state have been identified in PA. Understanding how these molecular abnormalities lead to excess aldosterone contributes significantly to the elucidation of the pathophysiology of low-renin hypertension. It may also lead to new and more effective therapies for this disease acting at the molecular level.
MeSH term(s)	Adenoma/complications ; Adenoma/genetics ; Adenoma/metabolism ; Adrenal Cortex Neoplasms/complications ; Adrenal Cortex Neoplasms/genetics ; Adrenal Cortex Neoplasms/metabolism ; Adrenal Gland Neoplasms/complications ; Adrenocortical Adenoma/complications ; Adrenocortical Adenoma/genetics ; Adrenocortical Adenoma/metabolism ; Aldosterone/metabolism ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; Humans ; Hyperaldosteronism/complications ; Hyperaldosteronism/genetics ; Hypertension/genetics ; Mutation ; Renin ; Sodium-Potassium-Exchanging ATPase/genetics ; Sodium-Potassium-Exchanging ATPase/metabolism
Chemical Substances	G Protein-Coupled Inwardly-Rectifying Potassium Channels ; KCNJ5 protein, human ; Aldosterone (4964P6T9RB) ; Renin (EC 3.4.23.15) ; Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13)
Language	English
Publishing date	2022-07-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2055373-0
ISSN	1534-3170 ; 1523-3782
ISSN (online)	1534-3170
ISSN	1523-3782
DOI	10.1007/s11886-022-01735-z
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Article ; Online: Genetic screening of hypertensive patients with aldosterone hypersecretion under conditions of stress.

Mourtzi, Niki / Sertedaki, Amalia / Markou, Athina / Piaditis, George P / Katsanis, Nicholas / Traeger-Synodinos, Joanne / Tsigos, Constantine / Charmandari, Evangelia

Hormones (Athens, Greece)

2022 Volume 21, Issue 4, Page(s) 525–536

Abstract: ... in ion-channels of aldosterone-regulating genes were prioritized. Variants with population frequency < 0.01 ... Purpose: Although ACTH is considered a secondary regulator of aldosterone production, patients ... of a well-characterized cohort of 21 hypertensive patients without PA but with stress-induced aldosterone ...

Abstract	Purpose: Although ACTH is considered a secondary regulator of aldosterone production, patients with apparent essential hypertension have been treated with mineralocorticoid receptor antagonists (MRAs). In this study, we aimed to identify potentially damaging variants that might be implicated in the phenotype of a well-characterized cohort of 21 hypertensive patients without PA but with stress-induced aldosterone hypersecretion. The patients' blood pressure was normalized though MRA administration. Methods: Genetic screening was performed through whole-exome sequencing (WES), and variants in PA-associated or in ion-channels of aldosterone-regulating genes were prioritized. Variants with population frequency < 0.01, predicted to alter protein structure and classified as likely pathogenic by in silico tools, were retained. Results: Qualifying variants were identified in nine of the 21 patients screened. Seven patients were carriers of six potentially damaging variants in six genes associated with PA (KCNK9, KCNK5, ATP13A3, SLC26A2, CACNA1H, and CACNA1D). A novel variant in the KCNK9 gene (p.V221M) is reported. Our analysis revealed two variants in two novel susceptibility genes for aldosterone hypersecretion, namely, KCNK16 (p.P255H) and CACNA2D3 (p.V557I). Conclusion: WES revealed potentially damaging germline variants in genes participating in aldosterone synthesis/regulating pathways in 9/21 patients of our cohort. The variants identified might play a role in aldosterone hypersecretion under conditions of stress. The potential pathogenicity of these variants should be examined in future functional studies.
MeSH term(s)	Humans ; Aldosterone/metabolism ; Genetic Testing ; Hyperaldosteronism/genetics ; Hyperaldosteronism/diagnosis ; Hypertension/drug therapy ; Hypertension/genetics ; Hypertension/complications ; Mineralocorticoid Receptor Antagonists
Chemical Substances	Aldosterone (4964P6T9RB) ; Mineralocorticoid Receptor Antagonists
Language	English
Publishing date	2022-08-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2075912-5
ISSN	2520-8721 ; 1109-3099
ISSN (online)	2520-8721
ISSN	1109-3099
DOI	10.1007/s42000-022-00394-7
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Article ; Online: Ion Channel Function and Electrical Excitability in the Zona Glomerulosa: A Network Perspective on Aldosterone Regulation.

Barrett, Paula Q / Guagliardo, Nick A / Bayliss, Douglas A

Annual review of physiology

2020 Volume 83, Page(s) 451–475

Abstract: ... somatic and germline mutations in ion channels in primary hyperaldosteronism underscores the importance ... Aldosterone excess is a pathogenic factor in many hypertensive disorders. The discovery of numerous ... periodic voltage spikes and coordinated bursts of Ca ...

Abstract	Aldosterone excess is a pathogenic factor in many hypertensive disorders. The discovery of numerous somatic and germline mutations in ion channels in primary hyperaldosteronism underscores the importance of plasma membrane conductances in determining the activation state of zona glomerulosa (zG) cells. Electrophysiological recordings describe an electrically quiescent behavior for dispersed zG cells. Yet, emerging data indicate that in native rosette structures in situ, zG cells are electrically excitable, generating slow periodic voltage spikes and coordinated bursts of Ca
MeSH term(s)	Aldosterone/metabolism ; Animals ; Calcium/metabolism ; Cell Communication/physiology ; Humans ; Ion Channels/metabolism ; Zona Glomerulosa/metabolism ; Zona Glomerulosa/physiology
Chemical Substances	Ion Channels ; Aldosterone (4964P6T9RB) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2020-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	207933-1
ISSN	1545-1585 ; 0066-4278
ISSN (online)	1545-1585
ISSN	0066-4278
DOI	10.1146/annurev-physiol-030220-113038
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Article ; Online: In situ metabolomics of aldosterone-producing adenomas.

Murakami, Masanori / Rhayem, Yara / Kunzke, Thomas / Sun, Na / Feuchtinger, Annette / Ludwig, Philippe / Strom, Tim Matthias / Gomez-Sanchez, Celso / Knösel, Thomas / Kirchner, Thomas / Williams, Tracy Ann / Reincke, Martin / Walch, Axel Karl / Beuschlein, Felix

JCI insight

2019 Volume 4, Issue 17

Abstract: ... primary aldosteronism. Matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron ... of aldosterone-producing adenomas (APAs). The objective of the current study was to produce a comprehensive, high ... Recent genetic examinations and multisteroid profiles have provided the basis for subclassification ...

Abstract	Recent genetic examinations and multisteroid profiles have provided the basis for subclassification of aldosterone-producing adenomas (APAs). The objective of the current study was to produce a comprehensive, high-resolution mass spectrometry imaging (MSI) map of APAs in relation to morphometry, immunohistochemical profiles, mutational status, and clinical outcome. The study cohort comprised 136 patients with unilateral primary aldosteronism. Matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance MSI was conducted, and metabolite profiles were analyzed with genotype/phenotype information, including digital image analysis from morphometry and IHC of steroidogenic enzymes. Distinct molecular signatures between KCNJ5- and CACNA1D-mutated APAs with significant differences of 137 metabolites, including metabolites of purine metabolism and steroidogenesis, were observed. Intratumor concentration of 18-oxocortisol and 18-hydroxycortisol were inversely correlated with the staining intensity of CYP11B1. Lower staining intensity of CYP11B1 and higher levels of 18-oxocortisol were associated with a higher probability of complete clinical success after surgery. The present study demonstrates distinct metabolomic profiles of APAs in relation to tumor genotype. In addition, we reveal an inverse correlation between cortisol derivatives and CYP11B1 and the impact of 18-oxocortisol and CYP11B1 on clinical outcome, which provides unprecedented insights into the pathophysiology, clinical features, and steroidogenesis of APAs.
MeSH term(s)	Adenoma/genetics ; Adenoma/metabolism ; Adrenal Cortex Neoplasms/genetics ; Adrenal Cortex Neoplasms/metabolism ; Adrenal Cortex Neoplasms/pathology ; Adrenocortical Adenoma/genetics ; Adrenocortical Adenoma/metabolism ; Adrenocortical Adenoma/pathology ; Adult ; Aldosterone/genetics ; Aldosterone/metabolism ; Calcium Channels, L-Type/metabolism ; Cohort Studies ; Female ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; Genotype ; Humans ; Hydrocortisone/analogs & derivatives ; Hydrocortisone/metabolism ; Hyperaldosteronism/metabolism ; Male ; Metabolomics/methods ; Middle Aged ; Mutation ; Phenotype ; Steroid 11-beta-Hydroxylase/metabolism
Chemical Substances	CACNA1D protein, human ; Calcium Channels, L-Type ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; KCNJ5 protein, human ; 18-oxocortisol (2410-60-8) ; Aldosterone (4964P6T9RB) ; Steroid 11-beta-Hydroxylase (EC 1.14.15.4) ; 18-hydroxycortisol (T8YUY43659) ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2019-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.130356
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