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Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance

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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 April 2021) | Viewed by 61533

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Prof. Dr. Michaela Adamcova

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Department of Physiology, Faculty of Medicine in Hradec Kralové, Charles University in Prague, Hradec Kralove, Czech Republic
Interests: cardiac remodeling; fibrosis; collagen; biomarkers of cardiac remodeling

Prof. Dr. Fedor Simko

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Institute of Pathophysiology, Faculty of Medicine, Comenius University, 81499 Bratislava, Slovakia
Interests: hypertension; RAAS; cardioprotective strategy; cardiac remodeling; heart failure

Dr. Ludovit Paulis

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Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
Interests: Alternative RAAS

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Dear Colleagues,

Renin-angiotensin-aldosterone system (RAAS) is a well-established player in the stress reaction. In its acute course, along with the sympathetic system, it helps to mobilize the circulation and substrates to enable high skeletal muscle activity. On the other hand, if chronically activated, the increased levels of angiotensin II and aldosterone in the circulation or tissues proved to activate the pathologic growth of myocytes and the proliferation of fibrocytes resulting in undesirable remodeling of the heart, kidney, brain and vessels. However, the omnipresent RAS represents an ingenious system of "checks and balances". Along with its vasoconstrictive, pro-proliferative, and pro-inflammatory receptors and compounds on one hand, molecules with opposing action on the other hand are emerging. These protective pathways of the RAS, counteracting the deleterious effect of angiotensin II or aldosterone, are mediated by angiotensin converting enzyme 2 (ACE2), angiotensin 1-7 and Mas and AT2 receptors. The angiotensin A/alamandine-MrgD receptor pathway seems to link the deleterious and protective branches of the RAS. The example of the complex impact of targeting this tricky system is represented by the limited benefit of the angiotensin converting inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) combination or by the perplex rationale of ACE2 substitution in the frame of COVID-19. Using ACEI or ARB may be both harmful by overstimulation of ACE2-COVID-19 binding receptor but also beneficial via stimulation of angiotensin II conversion to the protective Ang1-7 pathway. Thus, the aim of this Special Issue is to provide the latest insights into the complexity and interplay of the components of RAAS at molecular level, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular and other diseases.

Prof. Dr. Michaela Adamcova
Prof. Dr. Fedor Simko
Dr. Ludovit Paulis
Guest Editors

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Keywords

Cardiac remodeling
Fibrosis
Renin-angiotensin-aldosterone system
Angiotensin 1–7
Angiotensin 1–9
Angiotensin-converting enzyme 2
Type 2 angiotensin II receptor (AT₂R)
Proto-oncogene Mas receptor
Mas-related G protein-coupled receptor member D
Cardioprotective strategy
Severe acute respiratory syndrome coronavirus 2

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

8 pages, 405 KiB

Open AccessEditorial

Renin–Angiotensin–Aldosterone System: Friend or Foe—The Matter of Balance. Insight on History, Therapeutic Implications and COVID-19 Interactions

by Fedor Simko, Jaroslav Hrenak, Michaela Adamcova and Ludovit Paulis

Int. J. Mol. Sci. 2021, 22(6), 3217; https://doi.org/10.3390/ijms22063217 - 22 Mar 2021

Cited by 19 | Viewed by 7591

Abstract

The renin–angiotensin–aldosterone system (RAAS) ranks among the most challenging puzzles in cardiovascular medicine [...] Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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Research

Jump to: Editorial, Review

14 pages, 13487 KiB

Open AccessArticle

Cardioprotective Effects of a Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, in Dahl Salt-Sensitive Hypertensive Rats

by Asadur Rahman, Tatsuya Sawano, Anupoma Sen, Akram Hossain, Nourin Jahan, Hideki Kobara, Tsutomu Masaki, Shinji Kosaka, Kento Kitada, Daisuke Nakano, Takeshi Imamura, Hiroyuki Ohsaki and Akira Nishiyama

Int. J. Mol. Sci. 2021, 22(4), 2069; https://doi.org/10.3390/ijms22042069 - 19 Feb 2021

Cited by 15 | Viewed by 3399

Abstract

We investigated the effects of esaxerenone, a novel, nonsteroidal, and selective mineralocorticoid receptor blocker, on cardiac function in Dahl salt-sensitive (DSS) rats. We provided 6-week-old DSS rats a high-salt diet (HSD, 8% NaCl). Following six weeks of HSD feeding (establishment of cardiac hypertrophy), we divided the animals into the following two groups: HSD or HSD + esaxerenone (0.001%, w/w). In survival study, all HSD-fed animals died by 24 weeks of age, whereas the esaxerenone-treated HSD-fed animals showed significantly improved survival. We used the same protocol with a separate set of animals to evaluate the cardiac function by echocardiography after four weeks of treatment. The results showed that HSD-fed animals developed cardiac dysfunction as evidenced by reduced stroke volume, ejection fraction, and cardiac output. Importantly, esaxerenone treatment decreased the worsening of cardiac dysfunction concomitant with a significantly reduced level of systolic blood pressure. In addition, treatment with esaxerenone in HSD-fed DSS rats caused a reduced level of cardiac remodeling as well as fibrosis. Furthermore, inflammation and oxidative stress were significantly reduced. These data indicate that esaxerenone has the potential to mitigate cardiac dysfunction in salt-induced myocardial injury in rats. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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20 pages, 3344 KiB

Open AccessArticle

Deleterious Effects of Hyperactivity of the Renin-Angiotensin System and Hypertension on the Course of Chemotherapy-Induced Heart Failure after Doxorubicin Administration: A Study in Ren-2 Transgenic Rat

by Petr Kala, Hana Bartušková, Jan Piťha, Zdenka Vaňourková, Soňa Kikerlová, Šárka Jíchová, Vojtěch Melenovský, Lenka Hošková, Josef Veselka, Elzbieta Kompanowska-Jezierska, Janusz Sadowski, Olga Gawrys, Hana Maxová and Luděk Červenka

Int. J. Mol. Sci. 2020, 21(24), 9337; https://doi.org/10.3390/ijms21249337 - 8 Dec 2020

Cited by 15 | Viewed by 2559

Abstract

Doxorubicin’s (DOX) cardiotoxicity contributes to the development of chemotherapy-induced heart failure (HF) and new treatment strategies are in high demand. The aim of the present study was to characterize a DOX-induced model of HF in Ren-2 transgenic rats (TGR), those characterized by hypertension and hyperactivity of the renin-angiotensin-aldosterone system, and to compare the results with normotensive transgene-negative, Hannover Sprague-Dawley (HanSD) rats. DOX was administered for two weeks in a cumulative dose of 15 mg/kg. In HanSD rats DOX administration resulted in the development of an early phase of HF with the dominant symptom of bilateral cardiac atrophy demonstrable two weeks after the last DOX injection. In TGR, DOX caused substantial impairment of systolic function already at the end of the treatment, with further progression observed throughout the experiment. Additionally, two weeks after the termination of DOX treatment, TGR exhibited signs of HF characteristic for the transition stage between the compensated and decompensated phases of HF. In conclusion, we suggest that DOX-induced HF in TGR is a suitable model to study the pathophysiological aspects of chemotherapy-induced HF and to evaluate novel therapeutic strategies to combat this form of HF, which are urgently needed. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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Review

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17 pages, 13956 KiB

Open AccessReview

Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease

by Raúl Loera-Valencia, Francesca Eroli, Sara Garcia-Ptacek and Silvia Maioli

Int. J. Mol. Sci. 2021, 22(18), 10139; https://doi.org/10.3390/ijms221810139 - 20 Sep 2021

Cited by 36 | Viewed by 11350

Abstract

The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer’s disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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12 pages, 615 KiB

Open AccessReview

The Arcuate Nucleus of the Hypothalamus and Metabolic Regulation: An Emerging Role for Renin–Angiotensin Pathways

by Darren Mehay, Yuval Silberman and Amy C. Arnold

Int. J. Mol. Sci. 2021, 22(13), 7050; https://doi.org/10.3390/ijms22137050 - 30 Jun 2021

Cited by 13 | Viewed by 6920

Abstract

Obesity is a chronic state of energy imbalance that represents a major public health problem and greatly increases the risk for developing hypertension, hyperglycemia, and a multitude of related pathologies that encompass the metabolic syndrome. The underlying mechanisms and optimal treatment strategies for obesity, however, are still not fully understood. The control of energy balance involves the actions of circulating hormones on a widely distributed network of brain regions involved in the regulation of food intake and energy expenditure, including the arcuate nucleus of the hypothalamus. While obesity is known to disrupt neurocircuits controlling energy balance, including those in the hypothalamic arcuate nucleus, the pharmacological targeting of these central mechanisms often produces adverse cardiovascular and other off-target effects. This highlights the critical need to identify new anti-obesity drugs that can activate central neurocircuits to induce weight loss without negatively impacting blood pressure control. The renin–angiotensin system may provide this ideal target, as recent studies show this hormonal system can engage neurocircuits originating in the arcuate nucleus to improve energy balance without elevating blood pressure in animal models. This review will summarize the current knowledge of renin–angiotensin system actions within the arcuate nucleus for control of energy balance, with a focus on emerging roles for angiotensin II, prorenin, and angiotensin-(1–7) pathways. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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21 pages, 1466 KiB

Open AccessReview

Regulation of Monocytes/Macrophages by the Renin–Angiotensin System in Diabetic Nephropathy: State of the Art and Results of a Pilot Study

by Claudine Moratal, Audrey Laurain, Mourad Naïmi, Thibault Florin, Vincent Esnault, Jaap G. Neels, Nicolas Chevalier, Giulia Chinetti and Guillaume Favre

Int. J. Mol. Sci. 2021, 22(11), 6009; https://doi.org/10.3390/ijms22116009 - 2 Jun 2021

Cited by 12 | Viewed by 3941

Abstract

Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin–angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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28 pages, 1977 KiB

Open AccessReview

The Impact of microRNAs in Renin–Angiotensin-System-Induced Cardiac Remodelling

by Michaela Adamcova, Ippei Kawano and Fedor Simko

Int. J. Mol. Sci. 2021, 22(9), 4762; https://doi.org/10.3390/ijms22094762 - 30 Apr 2021

Cited by 23 | Viewed by 4887

Abstract

Current knowledge on the renin–angiotensin system (RAS) indicates its central role in the pathogenesis of cardiovascular remodelling via both hemodynamic alterations and direct growth and the proliferation effects of angiotensin II or aldosterone resulting in the hypertrophy of cardiomyocytes, the proliferation of fibroblasts, and inflammatory immune cell activation. The noncoding regulatory microRNAs has recently emerged as a completely novel approach to the study of the RAS. A growing number of microRNAs serve as mediators and/or regulators of RAS-induced cardiac remodelling by directly targeting RAS enzymes, receptors, signalling molecules, or inhibitors of signalling pathways. Specifically, microRNAs that directly modulate pro-hypertrophic, pro-fibrotic and pro-inflammatory signalling initiated by angiotensin II receptor type 1 (AT1R) stimulation are of particular relevance in mediating the cardiovascular effects of the RAS. The aim of this review is to summarize the current knowledge in the field that is still in the early stage of preclinical investigation with occasionally conflicting reports. Understanding the big picture of microRNAs not only aids in the improved understanding of cardiac response to injury but also leads to better therapeutic strategies utilizing microRNAs as biomarkers, therapeutic agents and pharmacological targets Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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16 pages, 3286 KiB

Open AccessReview

DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

by Yoshimichi Takeda, Masashi Demura, Takashi Yoneda and Yoshiyu Takeda

Int. J. Mol. Sci. 2021, 22(9), 4587; https://doi.org/10.3390/ijms22094587 - 27 Apr 2021

Cited by 20 | Viewed by 4734

Abstract

Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene CYP11B2 is regulated by angiotensin II and potassium. DNA methylation negatively regulates AGT and CYP11B2 expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the ATG promoter region, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac AGT expression. CpG dinucleotides in the CYP11B2 promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated CYP11B2 promoter. Low salt intake and angiotensin II infusion lead to upregulation of CYP11B2 expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases CYP11B2 expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased CYP11B2 expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both AGT and CYP11B2 contribute to the pathogenesis of cardiovascular diseases. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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22 pages, 4412 KiB

Open AccessReview

Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins

by Chien-Ning Hsu and You-Lin Tain

Int. J. Mol. Sci. 2021, 22(5), 2298; https://doi.org/10.3390/ijms22052298 - 25 Feb 2021

Cited by 57 | Viewed by 7790

Abstract

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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19 pages, 6586 KiB

Open AccessReview

Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome

by Jaroslav Hrenak and Fedor Simko

Int. J. Mol. Sci. 2020, 21(21), 8038; https://doi.org/10.3390/ijms21218038 - 28 Oct 2020

Cited by 57 | Viewed by 6765

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by massive inflammation, increased vascular permeability and pulmonary edema. Mortality due to ARDS remains very high and even in the case of survival, acute lung injury can lead to pulmonary fibrosis. The renin–angiotensin system (RAS) plays a significant role in these processes. The activities of RAS molecules are subject to dynamic changes in response to an injury. Initially, increased levels of angiotensin (Ang) II and des-Arg⁹-bradykinin (DABK), are necessary for an effective defense. Later, augmented angiotensin converting enzyme (ACE) 2 activity supposedly helps to attenuate inflammation. Appropriate ACE2 activity might be decisive in preventing immune-induced damage and ensuring tissue repair. ACE2 has been identified as a common target for different pathogens. Some Coronaviruses, including SARS-CoV-2, also use ACE2 to infiltrate the cells. A number of questions remain unresolved. The importance of ACE2 shedding, associated with the release of soluble ACE2 and ADAM17-mediated activation of tumor necrosis factor-α (TNF-α)-signaling is unclear. The roles of other non-classical RAS-associated molecules, e.g., alamandine, Ang A or Ang 1–9, also deserve attention. In addition, the impact of established RAS-inhibiting drugs on the pulmonary RAS is to be elucidated. The unfavorable prognosis of ARDS and the lack of effective treatment urge the search for novel therapeutic strategies. In the context of the ongoing SARS-CoV-2 pandemic and considering the involvement of humoral disbalance in the pathogenesis of ARDS, targeting the renin–angiotensin system and reducing the pathogen’s cell entry could be a promising therapeutic strategy in the struggle against COVID-19. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)

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