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Article ; Online: Pathophysiology of bilateral hyperaldosteronism.

Nanba, Kazutaka / Rainey, William E

Current opinion in endocrinology, diabetes, and obesity

2022 Volume 29, Issue 3, Page(s) 233–242

Abstract: Purpose of review: Renin-independent aldosterone production from one or both affected adrenal(s), a condition known as primary aldosteronism (PA), is a common cause of secondary hypertension. In this review, we aimed to summarize recent findings ... ...

Abstract	Purpose of review: Renin-independent aldosterone production from one or both affected adrenal(s), a condition known as primary aldosteronism (PA), is a common cause of secondary hypertension. In this review, we aimed to summarize recent findings regarding pathophysiology of bilateral forms of PA, including sporadic bilateral hyperaldosteronism (BHA) and rare familial hyperaldosteronism. Recent findings: The presence of subcapsular aldosterone synthase (CYP11B2)-expressing aldosterone-producing micronodules, also called aldosterone-producing cell clusters, appears to be a common histologic feature of adrenals with sporadic BHA. Aldosterone-producing micronodules frequently harbor aldosterone-driver somatic mutations. Other potential factors leading to sporadic BHA include rare disease-predisposing germline variants, circulating angiotensin II type 1 receptor autoantibodies, and paracrine activation of aldosterone production by adrenal mast cells. The application of whole exome sequencing has also identified new genes that cause inherited familial forms of PA. Summary: Research over the past 10 years has significantly improved our understanding of the molecular pathogenesis of bilateral PA. Based on the improved understanding of BHA, future studies should have the ability to develop more personalized treatment options and advanced diagnostic tools for patients with PA.
MeSH term(s)	Adrenal Glands/metabolism ; Aldosterone/metabolism ; Cytochrome P-450 CYP11B2/genetics ; Humans ; Hyperaldosteronism/physiopathology
Chemical Substances	Aldosterone (4964P6T9RB) ; Cytochrome P-450 CYP11B2 (EC 1.14.15.4)
Language	English
Publishing date	2022-05-03
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2272017-0
ISSN	1752-2978 ; 1752-296X
ISSN (online)	1752-2978
ISSN	1752-296X
DOI	10.1097/MED.0000000000000729
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Article ; Online: Progress in Primary Aldosteronism 7: No better time to meet!

Reincke, Martin / Rainey, William E / Williams, Tracy Ann

Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association

2023 Volume 131, Issue 7-08, Page(s) 383–385

MeSH term(s)	Humans ; Hyperaldosteronism/diagnosis ; Hyperaldosteronism/therapy ; Aldosterone ; Hypertension
Chemical Substances	Aldosterone (4964P6T9RB)
Language	English
Publishing date	2023-08-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1225416-2
ISSN	1439-3646 ; 0947-7349
ISSN (online)	1439-3646
ISSN	0947-7349
DOI	10.1055/a-2129-3672
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Article ; Online: GENETICS IN ENDOCRINOLOGY: Impact of race and sex on genetic causes of aldosterone-producing adenomas.

Nanba, Kazutaka / Rainey, William E

European journal of endocrinology

2021 Volume 185, Issue 1, Page(s) R1–R11

Abstract: Primary aldosteronism (PA) is a common cause of secondary hypertension. Recent technological advances in genetic analysis have provided a better understanding of the molecular pathogenesis of this disease. The application of next-generation sequencing ... ...

Abstract	Primary aldosteronism (PA) is a common cause of secondary hypertension. Recent technological advances in genetic analysis have provided a better understanding of the molecular pathogenesis of this disease. The application of next-generation sequencing has resulted in the identification of somatic mutations in aldosterone-producing adenoma (APA), a major subtype of PA. Based on the recent findings using a sequencing method that selectively targets the tumor region where aldosterone synthase (CYP11B2) is expressed, the vast majority of APAs appear to harbor a somatic mutation in one of the aldosterone-driver genes, including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. Mutations in these genes alter intracellular ion homeostasis and enhance aldosterone production. In a small subset of APAs, somatic activating mutations in the CTNNB1 gene, which encodes β-catenin, have also been detected. Accumulating evidence suggests that race and sex impact the somatic mutation spectrum of APA. Specifically, somatic mutations in the KCNJ5 gene, encoding an inwardly rectifying K+ channel, are common in APAs from Asian populations as well as women regardless of race. Associations between APA histology, genotype, and patient clinical characteristics have also been proposed, suggesting a potential need to consider race and sex for the management of PA patients. Herein, we review recent findings regarding somatic mutations in APA and discuss potential roles of race and sex on the pathophysiology of APA as well as possible clinical implications.
MeSH term(s)	Adrenal Cortex Neoplasms/complications ; Adrenal Cortex Neoplasms/ethnology ; Adrenal Cortex Neoplasms/genetics ; Adrenocortical Adenoma/complications ; Adrenocortical Adenoma/ethnology ; Adrenocortical Adenoma/genetics ; African Americans/genetics ; Asians/genetics ; Blacks/genetics ; CLC-2 Chloride Channels ; Calcium Channels, L-Type/genetics ; Calcium Channels, T-Type/genetics ; Chloride Channels/genetics ; Cytochrome P-450 CYP11B2/genetics ; Female ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics ; Humans ; Hyperaldosteronism/ethnology ; Hyperaldosteronism/etiology ; Hyperaldosteronism/genetics ; Male ; Plasma Membrane Calcium-Transporting ATPases/genetics ; Racial Groups/genetics ; Sex Factors ; Sodium-Potassium-Exchanging ATPase/genetics ; Steroid 11-beta-Hydroxylase/genetics ; Whites/genetics ; beta Catenin/genetics
Chemical Substances	CACNA1D protein, human ; CACNA1H protein, human ; CLC-2 Chloride Channels ; CTNNB1 protein, human ; Calcium Channels, L-Type ; Calcium Channels, T-Type ; Chloride Channels ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; KCNJ5 protein, human ; beta Catenin ; Cytochrome P-450 CYP11B2 (EC 1.14.15.4) ; Steroid 11-beta-Hydroxylase (EC 1.14.15.4) ; ATP1A1 protein, human (EC 3.6.1.-) ; Plasma Membrane Calcium-Transporting ATPases (EC 3.6.3.8) ; ATP2B3 protein, human (EC 7.2.2.10) ; Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13)
Language	English
Publishing date	2021-05-21
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1530/EJE-21-0031
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Article: [No title information]

Reincke, Martin / Rainey, William E. / Williams, Tracy Ann

Experimental and Clinical Endocrinology & Diabetes

2023 Volume 131, Issue 07/08, Page(s) 383–385

Keywords	aldosterone ; renin ; adrenal adenoma ; secondary hypertension ; endocrine hypertension
Language	English
Publishing date	2023-08-01
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	1225416-2
ISSN	1439-3646 ; 0947-7349
ISSN (online)	1439-3646
ISSN	0947-7349
DOI	10.1055/a-2129-3672
Database	Thieme publisher's database

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Article ; Online: The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease.

Lim, Jung Soo / Rainey, William E

Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme

2020 Volume 52, Issue 6, Page(s) 427–434

Abstract: Primary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. ... ...

Abstract	Primary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.
MeSH term(s)	Adrenal Cortex/cytology ; Adrenal Cortex/metabolism ; Adrenal Cortex/pathology ; Adrenal Cortex Neoplasms/genetics ; Adrenal Cortex Neoplasms/metabolism ; Adrenal Cortex Neoplasms/pathology ; Adrenal Glands/cytology ; Adrenal Glands/metabolism ; Adrenal Glands/pathology ; Adrenocortical Adenoma/genetics ; Adrenocortical Adenoma/metabolism ; Adrenocortical Adenoma/pathology ; Aldosterone/metabolism ; Cytochrome P-450 CYP11B2/genetics ; Cytochrome P-450 CYP11B2/metabolism ; High-Throughput Nucleotide Sequencing ; Humans ; Hyperaldosteronism/complications ; Hyperaldosteronism/genetics ; Hyperaldosteronism/metabolism ; Hyperaldosteronism/pathology ; Hypertension/etiology ; Hypertension/metabolism ; Hypertension/pathology ; Immunohistochemistry
Chemical Substances	Aldosterone (4964P6T9RB) ; Cytochrome P-450 CYP11B2 (EC 1.14.15.4)
Language	English
Publishing date	2020-03-30
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	80125-2
ISSN	1439-4286 ; 0018-5043
ISSN (online)	1439-4286
ISSN	0018-5043
DOI	10.1055/a-1128-0421
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Article ; Online: Introduction to the 2014 Adrenal Cortex Conference Keith L. Parker Memorial Lecturer: Bernard Schimmer, Ph.D.

Rainey, William E

Molecular and cellular endocrinology

2015 Volume 408, Page(s) 2–4

MeSH term(s)	Adrenal Cortex/physiology ; Endocrinology/history ; History, 20th Century ; History, 21st Century ; Humans ; United States
Language	English
Publishing date	2015-06-15
Publishing country	Ireland
Document type	Biography ; Historical Article ; Journal Article ; Portraits ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2014.12.018
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Article: Approaches to Gene Mutation Analysis Using Formalin-Fixed Paraffin-Embedded Adrenal Tumor Tissue From Patients With Primary Aldosteronism.

Nanba, Kazutaka / Rainey, William E / Udager, Aaron M

Frontiers in endocrinology

2021 Volume 12, Page(s) 683588

Abstract: Aldosterone production is physiologically under the control of circulating potassium and angiotensin II as well as adrenocorticotropic hormone and other secretagogues such as serotonin. The adrenal's capacity to produce aldosterone relies heavily on the ... ...

Abstract	Aldosterone production is physiologically under the control of circulating potassium and angiotensin II as well as adrenocorticotropic hormone and other secretagogues such as serotonin. The adrenal's capacity to produce aldosterone relies heavily on the expression of a single enzyme, aldosterone synthase (CYP11B2). This enzyme carries out the final reactions in the synthesis of aldosterone and is expressed almost solely in the adrenal zona glomerulosa. From a disease standpoint, primary aldosteronism (PA) is the most common of all adrenal disorders. PA results from renin-independent adrenal expression of CYP11B2 and production of aldosterone. The major causes of PA are adrenal aldosterone-producing adenomas (APA) and adrenal idiopathic hyperaldosteronism. Our understanding of the genetic causes of APA has significantly improved through comprehensive genetic profiling with next-generation sequencing. Whole-exome sequencing has led to the discovery of mutations in six genes that cause renin-independent aldosterone production and thus PA. To facilitate broad-based prospective and retrospective studies of APA, recent technologic advancements have allowed the determination of tumor mutation status using formalin-fixed paraffin-embedded (FFPE) tissue sections. This approach has the advantages of providing ready access to archival samples and allowing CYP11B2 immunohistochemistry-guided capture of the exact tissue responsible for inappropriate aldosterone synthesis. Herein we review the methods and approaches that facilitate the use of adrenal FFPE material for DNA capture, sequencing, and mutation determination.
MeSH term(s)	Adrenal Gland Neoplasms/genetics ; Adrenal Gland Neoplasms/metabolism ; Aldosterone/metabolism ; Cytochrome P-450 CYP11B2/metabolism ; DNA Mutational Analysis ; Fixatives ; Formaldehyde ; Humans ; Hyperaldosteronism/genetics ; Hyperaldosteronism/metabolism ; Mutation ; Paraffin Embedding
Chemical Substances	Fixatives ; Formaldehyde (1HG84L3525) ; Aldosterone (4964P6T9RB) ; Cytochrome P-450 CYP11B2 (EC 1.14.15.4)
Language	English
Publishing date	2021-06-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2021.683588
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Primary Cultures and Cell Lines for In Vitro Modeling of the Human Adrenal Cortex.

Nanba, Kazutaka / Blinder, Amy R / Rainey, William E

The Tohoku journal of experimental medicine

2021 Volume 253, Issue 4, Page(s) 217–232

Abstract: The human adrenal cortex is a complex endocrine organ that produces mineralocorticoids, glucocorticoids and androgens. These steroids are produced in distinct cell types located within the glomerulosa, fasciculata and reticularis of the adrenal cortex. ... ...

Abstract	The human adrenal cortex is a complex endocrine organ that produces mineralocorticoids, glucocorticoids and androgens. These steroids are produced in distinct cell types located within the glomerulosa, fasciculata and reticularis of the adrenal cortex. Abnormal adrenal steroidogenesis leads to a variety of diseases that can cause hypertension, metabolic syndrome, infertility and premature adrenarche. The adrenal cortex can also develop steroid-producing adenomas and rarely adrenocortical carcinomas. In vitro cell culture models provide important tools to study molecular and cellular mechanisms controlling both the physiologic and pathologic conditions of the adrenal cortex. In addition, the presence of multiple steroid-metabolizing enzymes within adrenal cells makes it a model for defining possible endocrine disruptors that might block these enzymes. The regulation and dysregulation of human adrenal steroid production and cell division/tumor growth can be studied using freshly isolated cells but this requires access to human adrenal glands, which are not available to most investigators. Immortalized human adrenocortical cell lines have proven to be of considerable value in studying the molecular and biochemical mechanisms controlling adrenal steroidogenesis and tumorigenesis. Current human adrenal cell lines include the original NCI-H295 and its substrains: H295A, H295R, HAC13, HAC15, HAC50 and H295RA as well as the recently established MUC-1, CU-ACC1 and CU-ACC2. The current review will discuss the use of primary cultures of fetal and adult adrenal cells as well as adrenocortical cell lines as in vitro models for the study of human adrenal physiology and pathophysiology.
MeSH term(s)	Adrenal Cortex/cytology ; Cell Line, Tumor ; Cells, Cultured ; Humans ; Models, Biological
Language	English
Publishing date	2021-04-12
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	123477-8
ISSN	1349-3329 ; 0040-8727
ISSN (online)	1349-3329
ISSN	0040-8727
DOI	10.1620/tjem.253.217
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Article: Primary aldosteronism diagnostics:

Rege, Juilee / Turcu, Adina F / Rainey, William E

Gland surgery

2020 Volume 9, Issue 1, Page(s) 3–13

Abstract: Primary aldosteronism (PA) is characterized by autonomous aldosterone production by renin-independent mechanisms and is most commonly sporadic. While 60-70% of sporadic PA can be attributed to bilateral hyperaldosteronism, the remaining 30-40% is caused ... ...

Abstract	Primary aldosteronism (PA) is characterized by autonomous aldosterone production by renin-independent mechanisms and is most commonly sporadic. While 60-70% of sporadic PA can be attributed to bilateral hyperaldosteronism, the remaining 30-40% is caused by a unilateral aldosterone-producing adenoma (APA). Somatic mutations in or near the selectivity filter the
Language	English
Publishing date	2020-03-23
Publishing country	China (Republic : 1949- )
Document type	Journal Article ; Review
ZDB-ID	3016969-0
ISSN	2227-8575 ; 2227-684X
ISSN (online)	2227-8575
ISSN	2227-684X
DOI	10.21037/gs.2019.10.22
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Concomitant Pheochromocytoma and Primary Aldosteronism: A Case Series and Literature Review.

Mao, Jimmy J / Baker, Jessica E / Rainey, William E / Young, William F / Bancos, Irina

Journal of the Endocrine Society

2021 Volume 5, Issue 8, Page(s) bvab107

Abstract: Context: The detection and management of concomitant pheochromocytoma (PHEO) and primary aldosteronism (PA) is not well understood.: Objective: To investigate varying presentations and outcomes of cases with coexisting PHEO and PA to provide an ... ...

Abstract	Context: The detection and management of concomitant pheochromocytoma (PHEO) and primary aldosteronism (PA) is not well understood. Objective: To investigate varying presentations and outcomes of cases with coexisting PHEO and PA to provide an approach to its diagnosis and management. Methods: We conducted a retrospective case series of adult patients with concomitant PHEO and PA at Mayo Clinic from 2000-2020 and an additional review of cases before 2000 and from the medical literature. Clinical, biochemical, radiologic, and histologic parameters were measured. Results: Fifteen patients (53% men, median age 53 years) were diagnosed with concomitant PHEO and PA. The majority presented with hypertension (13, 87%) and hypokalemia (13, 87%), and 6 (40%) presented with symptoms suggestive of catecholamine excess. All patients who underwent preoperative workup for catecholamine excess (14, 93%) were found to have biochemical levels above the upper limits of normal. Adrenal vein sampling (AVS) was performed in 9 patients (60%), where 5 (56%) were diagnosed with bilateral PA, and 4 (44%) with unilateral PA. Patients underwent either unilateral (12, 80%) or bilateral (3, 20%) adrenalectomy. Biochemical improvement or resolution of catecholamine excess was confirmed in all cases with documented measurements. Recurrence of PHEO was not observed. Six patients (40%) displayed persistent PA postoperatively. Conclusion: Concomitant PHEO and PA is a rare but likely underreported condition. Hypertension with or without hypokalemia should prompt evaluation for PA, while any indeterminate adrenal mass should be assessed for PHEO. Coexisting disease warrants consideration of AVS to determine the laterality of PA to ensure appropriate management.
Language	English
Publishing date	2021-06-16
Publishing country	United States
Document type	Journal Article
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/jendso/bvab107
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