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Molecular Advances in Aldosterone and Aldosterone Related Disorders
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Molecular Advances in Aldosterone and Aldosterone Related Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 11546

Special Issue Editor

Dr. Yoshiyu Takeda

E-Mail Website
Guest Editor
Kanazawa University School of Medicine, Kanazawa, Japan
Interests: hyperaldosteronism; low blood potassium; low potassium level; hypertension

Special Issue Information

Dear Colleagues,

Aldosterone plays an important role in the pathogenesis of cardiovascular, renal, and metabolic diseases. Aldosterone synthesis is regulated not only by angiotensin II and potassium but also substance P, indicating that the autonomic nervous system exerts a direct stimulatory role. A potential role of aldosterone-producing cell clusters (APCCs) in aldosterone-related disorders has been reported. Several somatic mutations in ion-channel genes have been implicated in the development of aldosterone-producing adenoma and APCCs. Mineralocorticoid receptors (MRs) exist in both epithelial and non-epithelial cells such as vascular endothelial and smooth muscle cells, cardiomyocytes, and adipocytes. Type II lung epithelial cells possess MRs, which may contribute to COVID-19 complications.

The purpose of this Special Issue is to highlight the molecular advances in aldosterone synthesis, and the pathophysiological roles of aldosterone and aldosterone-related disorders.

Dr. Yoshiyu Takeda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aldosterone
  • genome
  • epigenome
  • CYP11B2
  • mineralocorticoid receptor
  • aldosterone-related disorder

Published Papers (5 papers)

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Research

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13 pages, 1614 KiB  
Article
Comprehensive Steroid Assay with Non-Targeted Analysis Using Liquid Chromatography Ion Mobility Mass Spectrometry
by Mai Yamakawa, Shigehiro Karashima, Riko Takata, Taichi Haba, Keigo Kuroiwa, Hideaki Touyama, Atsushi Hashimoto, Seigo Konishi, Daisuke Aono, Mitsuhiro Kometani, Hidetaka Nambo, Takashi Yoneda and Issey Osaka
Int. J. Mol. Sci. 2022, 23(22), 13858; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213858 - 10 Nov 2022
Cited by 1 | Viewed by 1547
Abstract
Aldosterone-producing adenomas (APAs) have different steroid profiles in serum, depending on the causative genetic mutation. Ion mobility is a separation technique for gas-phase ions based on their m/z values, shapes, and sizes. Human serum (100 µL) was purified by liquid–liquid extraction [...] Read more.
Aldosterone-producing adenomas (APAs) have different steroid profiles in serum, depending on the causative genetic mutation. Ion mobility is a separation technique for gas-phase ions based on their m/z values, shapes, and sizes. Human serum (100 µL) was purified by liquid–liquid extraction using tert-butyl methyl ether/ethyl acetate at 1/1 (v/v) and mixed with deuterium-labeled steroids as the internal standard. The separated supernatant was dried, re-dissolved in water containing 20% methanol, and injected into a liquid chromatography–ion mobility–mass spectrometer (LC/IM/MS). We established a highly sensitive assay system by separating 20 steroids based on their retention time, m/z value, and drift time. Twenty steroids were measured in the serum of patients with primary aldosteronism, essential hypertension, and healthy subjects and were clearly classified using principal component analysis. This method was also able to detect phosphatidylcholine and phosphatidylethanolamine, which were not targeted. LC/IM/MS has a high selectivity for known compounds and has the potential to provide information on unknown compounds. This analytical method has the potential to elucidate the pathogenesis of APA and identify unknown steroids that could serve as biomarkers for APA with different genetic mutations. Full article
(This article belongs to the Special Issue Molecular Advances in Aldosterone and Aldosterone Related Disorders)
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10 pages, 1064 KiB  
Article
The Association of Cholesterol Uptake and Synthesis with Histology and Genotype in Cortisol-Producing Adenoma (CPA)
by Naoki Motomura, Yuto Yamazaki, Daiki Koga, Shogo Harashima, Xin Gao, Yuta Tezuka, Kei Omata, Yoshikiyo Ono, Ryo Morimoto, Fumitoshi Satoh, Yasuhiro Nakamura, Go Eun Kwon, Man Ho Choi, Akihiro Ito and Hironobu Sasano
Int. J. Mol. Sci. 2022, 23(4), 2174; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042174 - 16 Feb 2022
Cited by 2 | Viewed by 1666
Abstract
Cortisol-producing adenoma (CPA) is composed of clear and compact cells. Clear cells are lipid abundant, and compact ones lipid poor but associated with higher production of steroid hormones. PRKACA mutation (PRKACA mt) in CPA patients was reported to be associated with more [...] Read more.
Cortisol-producing adenoma (CPA) is composed of clear and compact cells. Clear cells are lipid abundant, and compact ones lipid poor but associated with higher production of steroid hormones. PRKACA mutation (PRKACA mt) in CPA patients was reported to be associated with more pronounced clinical manifestation of Cushing’s syndrome. In this study, we examined the association of histological features and genotypes with cholesterol uptake receptors and synthetic enzymes in 40 CPA cases, and with the quantitative results obtained by gas chromatography-mass spectrometry (GC-MS) analysis in 33 cases to explore their biological and clinical significance. Both cholesterol uptake receptors and synthetic enzymes were more abundant in compact cells. GC-MS analysis demonstrated that the percentage of compact cells was inversely correlated with the concentrations of cholesterol and cholesterol esters, and positively with the activity of cholesterol biosynthesis from cholesterol esters. In addition, hormone-sensitive lipase (HSL), which catalyzes cholesterol biosynthesis from cholesterol esters, tended to be more abundant in compact cells of PRKACA mt CPAs. These results demonstrated that both cholesterol uptake and biosynthesis were more pronounced in compact cells in CPA. In addition, more pronounced HSL expression in compact cells of PRKACA mt CPA could contribute to their more pronounced clinical manifestation. Full article
(This article belongs to the Special Issue Molecular Advances in Aldosterone and Aldosterone Related Disorders)
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Review

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21 pages, 750 KiB  
Review
Mineralocorticoid Receptor Antagonists for Preventing Chronic Kidney Disease Progression: Current Evidence and Future Challenges
by Wataru Fujii and Shigeru Shibata
Int. J. Mol. Sci. 2023, 24(9), 7719; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097719 - 23 Apr 2023
Cited by 3 | Viewed by 2467
Abstract
Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical analysis revealed how MR and the steroid hormone aldosterone integrate the responses of distinct tubular cells in the face of [...] Read more.
Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical analysis revealed how MR and the steroid hormone aldosterone integrate the responses of distinct tubular cells in the face of environmental perturbations and how their dysregulation compromises fluid homeostasis. In addition to these roles, the accumulation of data also provided unequivocal evidence that MR is involved in the pathophysiology of kidney diseases. Experimental studies delineated the diverse pathological consequences of MR overactivity and uncovered the multiple mechanisms that result in enhanced MR signaling. In parallel, clinical studies consistently demonstrated that MR blockade reduces albuminuria in patients with chronic kidney disease. Moreover, recent large-scale clinical studies using finerenone have provided evidence that the non-steroidal MR antagonist can retard the kidney disease progression in diabetic patients. In this article, we review experimental data demonstrating the critical importance of MR in mediating renal injury as well as clinical studies providing evidence on the renoprotective effects of MR blockade. We also discuss areas of future investigation, which include the benefit of non-steroidal MR antagonists in non-diabetic kidney disease patients, the identification of surrogate markers for MR signaling in the kidney, and the search for key downstream mediators whereby MR blockade confers renoprotection. Insights into these questions would help maximize the benefit of MR blockade in subjects with kidney diseases. Full article
(This article belongs to the Special Issue Molecular Advances in Aldosterone and Aldosterone Related Disorders)
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15 pages, 2483 KiB  
Review
Molecular and Epigenetic Control of Aldosterone Synthase, CYP11B2 and 11-Hydroxylase, CYP11B1
by Yoshimichi Takeda, Masashi Demura, Mitsuhiro Kometani, Shigehiro Karashima, Takashi Yoneda and Yoshiyu Takeda
Int. J. Mol. Sci. 2023, 24(6), 5782; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065782 - 17 Mar 2023
Cited by 4 | Viewed by 3009
Abstract
Aldosterone and cortisol serve important roles in the pathogenesis of cardiovascular diseases and metabolic disorders. Epigenetics is a mechanism to control enzyme expression by genes without changing the gene sequence. Steroid hormone synthase gene expression is regulated by transcription factors specific to each [...] Read more.
Aldosterone and cortisol serve important roles in the pathogenesis of cardiovascular diseases and metabolic disorders. Epigenetics is a mechanism to control enzyme expression by genes without changing the gene sequence. Steroid hormone synthase gene expression is regulated by transcription factors specific to each gene, and methylation has been reported to be involved in steroid hormone production and disease. Angiotensin II or potassium regulates the aldosterone synthase gene, CYP11B2. The adrenocorticotropic hormone controls the 11b-hydroxylase, CYP11B1. DNA methylation negatively controls the CYP11B2 and CYP11B1 expression and dynamically changes the expression responsive to continuous stimulation of the promoter gene. Hypomethylation status of the CYP11B2 promoter region is seen in aldosterone-producing adenomas. Methylation of recognition sites of transcription factors, including cyclic AMP responsive element binding protein 1 or nerve growth factor-induced clone B, diminish their DNA-binding activity. A methyl-CpG-binding protein 2 cooperates directly with the methylated CpG dinucleotides of CYP11B2. A low-salt diet, treatment with angiotensin II, and potassium increase the CYP11B2 mRNA levels and induce DNA hypomethylation in the adrenal gland. A close association between a low DNA methylation ratio and an increased CYP11B1 expression is seen in Cushing’s adenoma and aldosterone-producing adenoma with autonomous cortisol secretion. Epigenetic control of CYP11B2 or CYP11B1 plays an important role in autonomic aldosterone or cortisol synthesis. Full article
(This article belongs to the Special Issue Molecular Advances in Aldosterone and Aldosterone Related Disorders)
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15 pages, 1092 KiB  
Review
Clinical Translationality of KCNJ5 Mutation in Aldosterone Producing Adenoma
by Takumi Kitamoto and Tetsuo Nishikawa
Int. J. Mol. Sci. 2022, 23(16), 9042; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169042 - 12 Aug 2022
Cited by 4 | Viewed by 2133
Abstract
Hypertension due to primary aldosteronism poses a risk of severe cardiovascular complications compared to essential hypertension. The discovery of the KCNJ5 somatic mutation in aldosteroene producing adenoma (APA) in 2011 and the development of specific CYP11B2 antibodies in 2012 have greatly advanced our [...] Read more.
Hypertension due to primary aldosteronism poses a risk of severe cardiovascular complications compared to essential hypertension. The discovery of the KCNJ5 somatic mutation in aldosteroene producing adenoma (APA) in 2011 and the development of specific CYP11B2 antibodies in 2012 have greatly advanced our understanding of the pathophysiology of primary aldosteronism. In particular, the presence of CYP11B2-positive aldosterone-producing micronodules (APMs) in the adrenal glands of normotensive individuals and the presence of renin-independent aldosterone excess in normotensive subjects demonstrated the continuum of the pathogenesis of PA. Furthermore, among the aldosterone driver mutations which incur excessive aldosterone secretion, KCNJ5 was a major somatic mutation in APA, while CACNA1D is a leading somatic mutation in APMs and idiopathic hyperaldosteronism (IHA), suggesting a distinctive pathogenesis between APA and IHA. Although the functional detail of APMs has not been still uncovered, its impact on the pathogenesis of PA is gradually being revealed. In this review, we summarize the integrated findings regarding APA, APM or diffuse hyperplasia defined by novel CYP11B2, and aldosterone driver mutations. Following this, we discuss the clinical implications of KCNJ5 mutations to support better cardiovascular outcomes of primary aldosteronism. Full article
(This article belongs to the Special Issue Molecular Advances in Aldosterone and Aldosterone Related Disorders)
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