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Special Issue "Selected Papers from the Renin–Angiotensin–Aldosterone System (RAAS)2016: Official Satellite of ISH2016, from September 23 to 24 in Tokyo, Japan"

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 (13 February 2017)

Special Issue Editors

Guest Editor
Dr. Anastasia Susie Mihailidou

Department of Cardiology, Northern Sydney Local Health District and Kolling Institute, Sydney, Australia
E-Mail
Interests: hypertension management; blood pressure measurement and variability; cardiac molecular and cellular signalling pathways activated by aldosterone and cortisol; molecular mechanisms and translation research into diabetes; gender differences in ischemic heart disease; blood pressure variability during obstructive sleep apnoea and bereavement
Guest Editor
Prof. Dr. Jan Danser

Erasmus Medical Center, Department of Pharmacology and Vascular Medicine, Rotterdam, Zuid Holland, The Netherlands
Website | E-Mail
Interests: pharmacology and physiology of the renin–angiotensin–aldosterone system; ageing; diabetes; preeclampsia; VEGF inhibition/cancer; endothelin
Guest Editor
Prof. Dr. Sadayoshi Ito

Division of Nephrology, Endocrinology and Hypertension, Tohoku University Graduate School of Medicine, Sendai, Japan
Website | E-Mail
Interests: Renal Physiology; the renin angiotensin aldosterone; hypertension; clinical nephrology; endocrine hypertension
Guest Editor
Prof. Dr. Fumitoshi Satoh

Division of Clinical Hypertension, Endocrinology & Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan
Website | E-Mail
Interests: hypertension; endocine disease; chronic kidney disease; cardiovascular disease; diabetes melitus; etc.
Guest Editor
Prof. Dr. Akira Nishiyama

Kagawa University Medical School, Department of Pharmacology, Kagawa, Japan
Website | E-Mail
Interests: lifestyle-related diseases including hypertension; renal disease; diabetes; cardiovascular disease; cancer; etc.

Special Issue Information

Dear Colleagues,

Renin–angiotensin–aldosterone system (RAAS) blockers are the cornerstone of the treatment of cardiovascular disease and nephropathy. While there are currently four types of RAAS blockers (renin inhibitors, ACE inhibitors, AT1 receptor antagonists and mineralocorticoid receptor antagonists), there have been many exciting new developments as well as alternative RAAS targets identified. Recent investigations have revealed a range of unanticipated extrarenal actions of aldosterone, as well as detailed insight in the genetic causes of primary aldosteronism.

This Special Issue will present a selection of contributions from the two-day RAAS2016 Symposium (http://www.congre.co.jp/raas2016/) convened by Presidents Prof. Sadayoshi Ito (Sendai) and Prof. Jan Danser (Rotterdam) in Tokyo 23–24 September, 2016, immediately prior to the 26th Meeting of the International Society of Hypertension (ISH) which will be held in Seoul, Korea.

All speakers presenting a paper at this conference can submit a manuscript for publication. For further information contact the Editorial Office (ijms@mdpi.com).


Prof Sadayoshi Ito
Prof Jan Danser
Prof Akira Nishiyama
Prof Fumitoshi Satoh
Dr Anastasia S Mihailidou
Guest Editors

 

RAAS2016RAAS2016RAAS2016

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 papers will be 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 monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). 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

  • Renin–angiotensin–aldosterone system inhibitors
  • ACE2-angiotensin-(1-7)-Mas receptor
  • Combined AT1 receptor/neprilysin inhibitors (ARNI)
  • (Pro)renin receptor
  • Primary aldosteronism

Published Papers (8 papers)

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Research

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Open AccessArticle An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities
Int. J. Mol. Sci. 2017, 18(6), 1268; https://doi.org/10.3390/ijms18061268
Received: 29 January 2017 / Revised: 12 April 2017 / Accepted: 8 June 2017 / Published: 14 June 2017
Cited by 1 | PDF Full-text (2849 KB) | HTML Full-text | XML Full-text
Abstract
We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha
[...] Read more.
We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr). Both ion channels have also been shown to bind to Nedd4-2 via a conserved Proline-Tyrosine (PY) motif in C-terminal with subsequent ubiquitination and degradation by proteasome. Therefore, loss of Nedd4-2 C2 isoform might be involved in electrophysiological impairment under various conditions. We demonstrate here that Nedd4-2 C2 isoform causes cardiac conduction change in resting condition as well as proarrhythmic change after acute myocardial infarction (MI). The Nedd4-2 C2 knockout (KO) mice showed bradycardia, prolonged QRS, QT intervals, and suppressed PR interval in resting condition. In addition, enhancement of T peak/T end interval was found in mice with surgical ligation of the distal left coronary artery. Morphological analyses based on both ultrasonography of the living heart, as well as histopathological findings revealed that Nedd4-2 C2 KO mice show no significant structural changes from wild-type littermates under resting conditions. These results suggested that Nedd4-2 with C2 domain might play an important role in cardio-renal syndrome through post-transcriptional modification of both ENaC and cardiac ion channels, which are critical for kidney and heart functions. Full article
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Open AccessArticle Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice
Int. J. Mol. Sci. 2017, 18(6), 1250; https://doi.org/10.3390/ijms18061250
Received: 29 January 2017 / Revised: 29 May 2017 / Accepted: 7 June 2017 / Published: 11 June 2017
Cited by 1 | PDF Full-text (1607 KB) | HTML Full-text | XML Full-text
Abstract
The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN
[...] Read more.
The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination. Full article
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Open AccessArticle Clinical Utility of the Adrenocorticotropin Stimulation Test with/without Dexamethasone Suppression for Definitive and Subtype Diagnosis of Primary Aldosteronism
Int. J. Mol. Sci. 2017, 18(5), 948; https://doi.org/10.3390/ijms18050948
Received: 23 January 2017 / Revised: 11 March 2017 / Accepted: 27 April 2017 / Published: 30 April 2017
Cited by 2 | PDF Full-text (499 KB) | HTML Full-text | XML Full-text
Abstract
The adrenocorticotropin (ACTH) stimulation test (AST) has been reported to be useful for diagnosing primary aldosteronism (PA), particularly for differentiating PA subtypes under 1-mg dexamethasone suppression (DS). The aim of our study was to clarify the effect of 1-mg DS on AST results.
[...] Read more.
The adrenocorticotropin (ACTH) stimulation test (AST) has been reported to be useful for diagnosing primary aldosteronism (PA), particularly for differentiating PA subtypes under 1-mg dexamethasone suppression (DS). The aim of our study was to clarify the effect of 1-mg DS on AST results. A retrospective cohort study was conducted using data for 48 patients (PA: 30/48). We estimated the difference in plasma aldosterone concentration (PAC) responsiveness to ACTH stimulation with single (AST alone) and combined (AST under 1-mg DS) tests within the same patient. We compared the diagnostic accuracy of these two tests for PA and the laterality of hyperaldosteronism. We found no differences in PAC responsiveness to ACTH stimulation between single and combined tests, and observed a significant positive linear relationship (30 min, R2 = 0.75, p-value < 0.01). Both tests showed the highest diagnostic accuracy for PA following 30 min of ACTH stimulation. The ability to detect the laterality of hyperaldosteronism was inconsistent and differed according to the two definitions: lateralization ratio and the absolute aldosterone levels in adrenal venous sampling. PAC responsiveness to ACTH stimulation was similar for AST with and without 1-mg DS. AST can be performed under both conditions with similar accuracy to detect PA. Full article
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Open AccessArticle ATRAP Expression in Brown Adipose Tissue Does Not Influence the Development of Diet-Induced Metabolic Disorders in Mice
Int. J. Mol. Sci. 2017, 18(3), 676; https://doi.org/10.3390/ijms18030676
Received: 28 January 2017 / Revised: 9 March 2017 / Accepted: 16 March 2017 / Published: 21 March 2017
Cited by 2 | PDF Full-text (14234 KB) | HTML Full-text | XML Full-text
Abstract
Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions
[...] Read more.
Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAPfl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAPadipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAPfl/fl mice, ATRAPadipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAPfl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAPadipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders. Full article
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Review

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Open AccessReview Soluble (Pro)renin Receptor and Obstructive Sleep Apnea Syndrome: Oxidative Stress in Brain?
Int. J. Mol. Sci. 2017, 18(6), 1313; https://doi.org/10.3390/ijms18061313
Received: 24 April 2017 / Revised: 8 June 2017 / Accepted: 15 June 2017 / Published: 20 June 2017
Cited by 2 | PDF Full-text (1032 KB) | HTML Full-text | XML Full-text
Abstract
(Pro)renin receptor ((P)RR) is a multi-functional molecule that is related to both the renin-angiotensin system (RAS) and vacuolar H+-ATPase (v-ATPase), an ATP-dependent multi-subunit proton pump. Soluble (P)RR (s(P)RR), which consists of the extracellular domain of (P)RR, is present in blood and
[...] Read more.
(Pro)renin receptor ((P)RR) is a multi-functional molecule that is related to both the renin-angiotensin system (RAS) and vacuolar H+-ATPase (v-ATPase), an ATP-dependent multi-subunit proton pump. Soluble (P)RR (s(P)RR), which consists of the extracellular domain of (P)RR, is present in blood and urine. Elevated plasma s(P)RR concentrations are reported in patients with chronic kidney disease and pregnant women with hypertension or diabetes mellitus. In addition, we have shown that plasma s(P)RR concentrations are elevated in patients with obstructive sleep apnea syndrome (OSAS). Interestingly, the levels are elevated in parallel with the severity of OSAS, but are not related to the presence of hypertension or the status of the circulating RAS in OSAS. It is known that v-ATPase activity protects cells from endogenous oxidative stress, and loss of v-ATPase activity results in chronic oxidative stress. We hypothesize that hypoxia and subsequent oxidative stress, perhaps in the brain, may be one of the factors that elevate plasma s(P)RR levels in OSAS. Full article
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Graphical abstract

Open AccessReview Subtype Diagnosis of Primary Aldosteronism: Is Adrenal Vein Sampling Always Necessary?
Int. J. Mol. Sci. 2017, 18(4), 848; https://doi.org/10.3390/ijms18040848
Received: 16 March 2017 / Revised: 11 April 2017 / Accepted: 12 April 2017 / Published: 17 April 2017
Cited by 2 | PDF Full-text (251 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Aldosterone producing adenoma and bilateral adrenal hyperplasia are the two most common subtypes of primary aldosteronism (PA) that require targeted and distinct therapeutic approaches: unilateral adrenalectomy or lifelong medical therapy with mineralocorticoid receptor antagonists. According to the 2016 Endocrine Society Guideline, adrenal venous
[...] Read more.
Aldosterone producing adenoma and bilateral adrenal hyperplasia are the two most common subtypes of primary aldosteronism (PA) that require targeted and distinct therapeutic approaches: unilateral adrenalectomy or lifelong medical therapy with mineralocorticoid receptor antagonists. According to the 2016 Endocrine Society Guideline, adrenal venous sampling (AVS) is the gold standard test to distinguish between unilateral and bilateral aldosterone overproduction and therefore, to safely refer patients with PA to surgery. Despite significant advances in the optimization of the AVS procedure and the interpretation of hormonal data, a standardized protocol across centers is still lacking. Alternative methods are sought to either localize an aldosterone producing adenoma or to predict the presence of unilateral disease and thereby substantially reduce the number of patients with PA who proceed to AVS. In this review, we summarize the recent advances in subtyping PA for the diagnosis of unilateral and bilateral disease. We focus on the developments in the AVS procedure, the interpretation criteria, and comparisons of the performance of AVS with the alternative methods that are currently available. Full article
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Graphical abstract

Open AccessReview ACTH and Polymorphisms at Steroidogenic Loci as Determinants of Aldosterone Secretion and Blood Pressure
Int. J. Mol. Sci. 2017, 18(3), 579; https://doi.org/10.3390/ijms18030579
Received: 10 February 2017 / Revised: 28 February 2017 / Accepted: 2 March 2017 / Published: 7 March 2017
Cited by 1 | PDF Full-text (220 KB) | HTML Full-text | XML Full-text
Abstract
The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by
[...] Read more.
The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by data from genome-wide association studies that consistently link the CYP17A1 locus to blood pressure. In this review article, we describe common polymorphisms at three steroidogenic loci (CYP11B2, CYP11B1 and CYP17A1) that alter gene transcription efficiency and levels of key steroids, including aldosterone. However, the mechanism by which this occurs remains unclear. While the renin angiotensin system is rightly regarded as the major driver of aldosterone secretion, there is increasing evidence that the contribution of corticotropin (ACTH) is also significant. In light of this, we propose that the differential response of variant CYP11B2, CYP11B1 and CYP17A1 genes to ACTH is an important determinant of blood pressure, tending to predispose individuals with an unfavourable genotype to hypertension. Full article

Other

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Open AccessConference Report Aldosterone and Mineralocorticoid Receptors—Physiology and Pathophysiology
Int. J. Mol. Sci. 2017, 18(5), 1032; https://doi.org/10.3390/ijms18051032
Received: 8 March 2017 / Revised: 2 May 2017 / Accepted: 4 May 2017 / Published: 11 May 2017
Cited by 11 | PDF Full-text (1693 KB) | HTML Full-text | XML Full-text
Abstract
Aldosterone is a uniquely terrestrial hormone, first appearing in lungfish, which have both gills and lungs. Mineralocorticoid receptors (MRs), on the other hand, evolved much earlier, and are found in cartilaginous and bony fish, presumptive ligand cortisol. MRs have equivalent high affinity for
[...] Read more.
Aldosterone is a uniquely terrestrial hormone, first appearing in lungfish, which have both gills and lungs. Mineralocorticoid receptors (MRs), on the other hand, evolved much earlier, and are found in cartilaginous and bony fish, presumptive ligand cortisol. MRs have equivalent high affinity for aldosterone, progesterone, and cortisol; in epithelia, despite much higher cortisol circulating levels, aldosterone selectively activates MRs by co-expression of the enzyme 11β-hydroxysteroid dehydrogenase, Type 11. In tissues in which the enzyme is not expressed, MRs are overwhelmingly occupied but not activated by cortisol, which normally thus acts as an MR antagonist; in tissue damage, however, cortisol mimics aldosterone and acts as an MR agonist. The risk profile for primary aldosteronism (PA) is much higher than that in age-, sex-, and blood pressure-matched essential hypertensives. High levels of aldosterone per se are not the problem: in chronic sodium deficiency, as seen in the monsoon season in the highlands of New Guinea, plasma aldosterone levels are extraordinarily high, but cause neither hypertension nor cardiovascular damage. Such damage occurs when aldosterone levels are out of the normal feedback control, and are inappropriately elevated for the salt status of the individual (or experimental animal). The question thus remains of how excess salt can synergize with elevated aldosterone levels to produce deleterious cardiovascular effects. One possible mechanism is through the agency of the elusive ouabain-like factors (OLFs). Such factors are secreted from the adrenal in response to ACTH (adrenalocortical tropic hormone), to angiotensin via AT2R, and—the polar opposite of aldosterone—to sodium loading. They act on blood vessels to cause vasoconstriction and thus elevate blood pressure to dump excess sodium through pressure natriuresis. Their levels are chronically elevated in PA in response to the continually elevated sodium status, and they thus act to constrict coronary and systemic arteries. In the context of the elevated blood volume and total body sodium in a PA patient, this raises blood pressure and acts as the proximate cause of cardiovascular damage. If this is the case, it would appear to offer new insights into therapy for PA. One would be the use of digibindin, or its more recent successors as antagonists of OLFs acting on Na/K ATPase at the vessel wall. A second would be to routinely combine a low dose MR antagonist, an ENaC inhibitor, and sodium restriction as first-line therapy for bilateral aldosterone overproduction. Finally, for unilateral cases post-surgery, there is good reason to include low-dose MRs in drug therapy if required, given the ability of cortisol in damaged blood vessels to mimic aldosterone vasoconstrictor action. Full article
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