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Renin–Angiotensin–Aldosterone System
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Renin–Angiotensin–Aldosterone System

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (1 June 2021) | Viewed by 49833

Special Issue Editor

Dr. András Balla

E-Mail Website
Guest Editor
Semmelweis Egyetem, Budapest, Hungary
Interests: physiology; signal transduction; G-protein-coupled receptors (GPCRs); angiotensin II
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The aim of this Special Issue is to provide an overview of the latest findings and methods used in renin–angiotensin–aldosterone system (RAAS) research. Angiotensin II (Ang II) is an octapeptide hormone and is the main regulator of the renin–angiotensin system (RAS) that participates not only in physiological mechanisms but also in pathological ones. Ang II can bind and activate two types of angiotensin receptors (type 1 and type 2), and pleiotropic angiotensin signaling has become one of the most studied topics in molecular pharmacology. The angiotensin receptors play an important role in the regulation of the cardiovascular system, salt–water homeostasis, and in the development of pathological conditions such as hypertension, heart failure, cardiovascular remodeling, renal fibrosis, inflammation, and metabolic disorders. Better understanding of the complexity of the RAS and angiotensin signalling including the cross-talk between the pathways and functional selectivity of the ligands, new concepts and translational research in this field may offer new therapeutic opportunities and can lead to the development of novel type of drugs for the treatment of cardiovascular and other diseases.

This Special Issue of Cells therefore invites review articles and original research papers covering the angiotensin and RAS/RAAS research field.

Dr. András Balla
Guest Editor

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Keywords

  • renin–angiotensin–aldosterone system (RAS, RAAS)
  • signaling mechanisms of angiotensin receptors
  • GPCR
  • AT1R
  • angiotensin
  • signal transduction
  • biased agonism
  • functional selectivity
  • cardiovascular system
  • hypertension

Published Papers (16 papers)

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22 pages, 19538 KiB  
Article
Characterization of Type 1 Angiotensin II Receptor Activation Induced Dual-Specificity MAPK Phosphatase Gene Expression Changes in Rat Vascular Smooth Muscle Cells
by Janka Borbála Gém, Kinga Bernadett Kovács, Laura Szalai, Gyöngyi Szakadáti, Edit Porkoláb, Bence Szalai, Gábor Turu, András Dávid Tóth, Mária Szekeres, László Hunyady and András Balla
Cells 2021, 10(12), 3538; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123538 - 15 Dec 2021
Cited by 6 | Viewed by 3483
Abstract
Activation of the type I angiotensin receptor (AT1-R) in vascular smooth muscle cells (VSMCs) plays a crucial role in the regulation of blood pressure; however, it is also responsible for the development of pathological conditions such as vascular remodeling, hypertension and atherosclerosis. Stimulation [...] Read more.
Activation of the type I angiotensin receptor (AT1-R) in vascular smooth muscle cells (VSMCs) plays a crucial role in the regulation of blood pressure; however, it is also responsible for the development of pathological conditions such as vascular remodeling, hypertension and atherosclerosis. Stimulation of the VSMC by angiotensin II (AngII) promotes a broad variety of biological effects, including gene expression changes. In this paper, we have taken an integrated approach in which an analysis of AngII-induced gene expression changes has been combined with the use of small-molecule inhibitors and lentiviral-based gene silencing, to characterize the mechanism of signal transduction in response to AngII stimulation in primary rat VSMCs. We carried out Affymetrix GeneChip experiments to analyze the effects of AngII stimulation on gene expression; several genes, including DUSP5, DUSP6, and DUSP10, were identified as upregulated genes in response to stimulation. Since various dual-specificity MAPK phosphatase (DUSP) enzymes are important in the regulation of mitogen-activated protein kinase (MAPK) signaling pathways, these genes have been selected for further analysis. We investigated the kinetics of gene-expression changes and the possible signal transduction processes that lead to altered expression changes after AngII stimulation. Our data shows that the upregulated genes can be stimulated through multiple and synergistic signal transduction pathways. We have also found in our gene-silencing experiments that epidermal growth factor receptor (EGFR) transactivation is not critical in the AngII-induced expression changes of the investigated genes. Our data can help us understand the details of AngII-induced long-term effects and the pathophysiology of AT1-R. Moreover, it can help to develop potential interventions for those symptoms that are induced by the over-functioning of this receptor, such as vascular remodeling, cardiac hypertrophy or atherosclerosis. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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13 pages, 1231 KiB  
Article
Human Tissue Angiotensin Converting Enzyme (ACE) Activity Is Regulated by Genetic Polymorphisms, Posttranslational Modifications, Endogenous Inhibitors and Secretion in the Serum, Lungs and Heart
by Viktor Bánhegyi, Attila Enyedi, Gábor Áron Fülöp, Attila Oláh, Ivetta Mányiné Siket, Csongor Váradi, Klaudia Bottyán, Mária Lódi, Alexandra Csongrádi, Azeem J. Umar, Miklós Fagyas, Dániel Czuriga, István Édes, Miklós Pólos, Béla Merkely, Zoltán Csanádi, Zoltán Papp, Gábor Szabó, Tamás Radovits, István Takács and Attila Tóthadd Show full author list remove Hide full author list
Cells 2021, 10(7), 1708; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071708 - 06 Jul 2021
Cited by 11 | Viewed by 3028
Abstract
Objective: Inhibitors of the angiotensin converting enzyme (ACE) are the primarily chosen drugs to treat heart failure and hypertension. Moreover, an imbalance in tissue ACE/ACE2 activity is implicated in COVID-19. In the present study, we tested the relationships between circulating and tissue (lung [...] Read more.
Objective: Inhibitors of the angiotensin converting enzyme (ACE) are the primarily chosen drugs to treat heart failure and hypertension. Moreover, an imbalance in tissue ACE/ACE2 activity is implicated in COVID-19. In the present study, we tested the relationships between circulating and tissue (lung and heart) ACE levels in men. Methods: Serum, lung (n = 91) and heart (n = 72) tissue samples were collected from Caucasian patients undergoing lung surgery or heart transplantation. ACE I/D genotype, ACE concentration and ACE activity were determined from serum and tissue samples. Clinical parameters were also recorded. Results: A protocol for ACE extraction was developed for tissue ACE measurements. Extraction of tissue-localized ACE was optimal in a 0.3% Triton-X-100 containing buffer, resulting in 260 ± 12% higher ACE activity over detergent-free conditions. SDS or higher Triton-X-100 concentrations inhibited the ACE activity. Serum ACE concentration correlated with ACE I/D genotype (II: 166 ± 143 ng/mL, n = 19, ID: 198 ± 113 ng/mL, n = 44 and DD: 258 ± 109 ng/mL, n = 28, p < 0.05) as expected. In contrast, ACE expression levels in the lung tissue were approximately the same irrespective of the ACE I/D genotype (II: 1423 ± 1276 ng/mg, ID: 1040 ± 712 ng/mg and DD: 930 ± 1273 ng/mg, p > 0.05) in the same patients (values are in median ± IQR). Moreover, no correlations were found between circulating and lung tissue ACE concentrations and activities (Spearman’s p > 0.05). In contrast, a significant correlation was identified between ACE activities in serum and heart tissues (Spearman’s Rho = 0.32, p < 0.01). Finally, ACE activities in lung and the serum were endogenously inhibited to similar degrees (i.e., to 69 ± 1% and 53 ± 2%, respectively). Conclusion: Our data suggest that circulating ACE activity correlates with left ventricular ACE, but not with lung ACE in human. More specifically, ACE activity is tightly coordinated by genotype-dependent expression, endogenous inhibition and secretion mechanisms. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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16 pages, 6405 KiB  
Article
Overexpression of Transcripts Coding for Renin-b but Not for Renin-a Reduce Oxidative Stress and Increase Cardiomyoblast Survival under Starvation Conditions
by Heike Wanka, Philipp Lutze, Alexander Albers, Janine Golchert, Doreen Staar and Jörg Peters
Cells 2021, 10(5), 1204; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051204 - 14 May 2021
Cited by 5 | Viewed by 1630
Abstract
A stimulated renin-angiotensin system is known to promote oxidative stress, apoptosis, necrosis and fibrosis. Renin transcripts (renin-b; renin-c) encoding a cytosolic renin isoform have been discovered that may in contrast to the commonly known secretory renin (renin-a) exert protective effects Here, we analyzed [...] Read more.
A stimulated renin-angiotensin system is known to promote oxidative stress, apoptosis, necrosis and fibrosis. Renin transcripts (renin-b; renin-c) encoding a cytosolic renin isoform have been discovered that may in contrast to the commonly known secretory renin (renin-a) exert protective effects Here, we analyzed the effect of renin-a and renin-b overexpression in H9c2 cardiomyoblasts on apoptosis and necrosis as well as on potential mechanisms involved in cell death processes. To mimic ischemic conditions, cells were exposed to glucose starvation, anoxia or combined oxygen–glucose deprivation (OGD) for 24 h. Under OGD, control cells exhibited markedly increased necrotic and apoptotic cell death accompanied by enhanced ROS accumulation, loss of mitochondrial membrane potential and decreased ATP levels. The effects of OGD on necrosis were exaggerated in renin-a cells, but markedly diminished in renin-b cells. However, with respect to apoptosis, the effects of OGD were almost completely abolished in renin-b cells but interestingly also moderately diminished in renin-a cells. Under glucose depletion we found opposing responses between renin-a and renin-b cells; while the rate of necrosis and apoptosis was aggravated in renin-a cells, it was attenuated in renin-b cells. Based on our results, strategies targeting the regulation of cytosolic renin-b as well as the identification of pathways involved in the protective effects of renin-b may be helpful to improve the treatment of ischemia-relevant diseases. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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14 pages, 4660 KiB  
Article
Differential Effects of Angiotensin-II Compared to Phenylephrine on Arterial Stiffness and Hemodynamics: A Placebo-Controlled Study in Healthy Humans
by Klaas F. Franzen, Moritz Meusel, Julia Engel, Tamara Röcker, Daniel Drömann and Friedhelm Sayk
Cells 2021, 10(5), 1108; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051108 - 05 May 2021
Cited by 3 | Viewed by 2171
Abstract
The α1-adrenoceptor agonist phenylephrine (PE) and Angiotensin II (Ang II) are both potent vasoconstrictors at peripheral resistance arteries. PE has pure vasoconstrictive properties. Ang II, additionally, modulates central nervous blood pressure (BP) control via sympathetic baroreflex resetting. However, it is unknown [...] Read more.
The α1-adrenoceptor agonist phenylephrine (PE) and Angiotensin II (Ang II) are both potent vasoconstrictors at peripheral resistance arteries. PE has pure vasoconstrictive properties. Ang II, additionally, modulates central nervous blood pressure (BP) control via sympathetic baroreflex resetting. However, it is unknown whether Ang II vs. PE mediated vasoconstriction at equipressor dose uniformly or specifically modifies arterial stiffness. We conducted a three-arm randomized placebo-controlled cross-over trial in 30 healthy volunteers (15 female) investigating the effects of Ang II compared to PE at equal systolic pressor dose on pulse wave velocity (PWV), pulse wave reflection (augmentation index normalized to heart rate 75/min, AIx) and non-invasive hemodynamics by Mobil-O-Graph™ and circulating core markers of endothelial (dys-)function. PE but not Ang II-mediated hypertension induced a strong reflex-decrease in cardiac output. Increases in PWV, AIx, total peripheral resistance and pulse pressure, in contrast, were stronger during PE compared to Ang II at equal mean aortic BP. This was accompanied by minute changes in circulating markers of endothelial function. Moreover, we observed differential hemodynamic changes after stopping either vasoactive infusion. Ang II- and PE-mediated BP increase specifically modifies arterial stiffness and hemodynamics with aftereffects lasting beyond mere vasoconstriction. This appears attributable in part to different interactions with central nervous BP control including modified baroreflex function. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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13 pages, 4576 KiB  
Article
Effect of Hydrocortisone on Angiotensinogen (AGT) Mutation–Causing Autosomal Recessive Renal Tubular Dysgenesis
by Min-Hua Tseng, Shih-Ming Huang, Martin Konrad, Jing-Long Huang, Steven W. Shaw, Ya-Chung Tian, Ho-Yen Chueh, Wen-Lang Fan, Tai-Wei Wu, Jhao-Jhuang Ding, Ming-Chou Chiang and Shih-Hua Lin
Cells 2021, 10(4), 782; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040782 - 01 Apr 2021
Cited by 2 | Viewed by 2242
Abstract
We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen [...] Read more.
We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this AGT mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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15 pages, 4519 KiB  
Article
Angiotensin II-Induced Cardiac Effects Are Modulated by Endocannabinoid-Mediated CB1 Receptor Activation
by Zsuzsanna Miklós, Dina Wafa, György L. Nádasy, Zsuzsanna E. Tóth, Balázs Besztercei, Gabriella Dörnyei, Zsófia Laska, Zoltán Benyó, Tamás Ivanics, László Hunyady and Mária Szekeres
Cells 2021, 10(4), 724; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040724 - 24 Mar 2021
Cited by 8 | Viewed by 2277
Abstract
Angiotensin II (Ang II) has various cardiac effects and causes vasoconstriction. Ang II activates the type-1 angiotensin receptor—Gq/11 signaling pathway resulting in the release of 2-arachidonoylglycerol (2-AG). We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to [...] Read more.
Angiotensin II (Ang II) has various cardiac effects and causes vasoconstriction. Ang II activates the type-1 angiotensin receptor—Gq/11 signaling pathway resulting in the release of 2-arachidonoylglycerol (2-AG). We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to identify the role of type-1 cannabinoid receptors (CB1R) in these effects. Expression of CB1R in rat cardiac tissue was confirmed by immunohistochemistry. To characterize short-term Ang II effects, increasing concentrations of Ang II (10−9–10−7 M); whereas to assess tachyphylaxis, repeated infusions of Ang II (10−7 M) were administered to isolated Langendorff-perfused rat hearts. Ang II infusions caused a decrease in coronary flow and ventricular inotropy, which was more pronounced during the first administration. CB agonist 2-AG and WIN55,212-2 administration to the perfusate enhanced coronary flow. The flow-reducing effect of Ang II was moderated in the presence of CB1R blocker O2050 and diacylglycerol-lipase inhibitor Orlistat. Our findings indicate that Ang II-induced cardiac effects are modulated by simultaneous CB1R-activation, most likely due to 2-AG-release during Ang II signalling. In this combined effect, the response to 2-AG via cardiac CB1R may counteract the positive inotropic effect of Ang II, which may decrease metabolic demand and augment Ang II-induced coronary vasoconstriction. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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16 pages, 4126 KiB  
Article
The Angiotensin II Receptor Blocker Losartan Sensitizes Human Liver Cancer Cells to Lenvatinib-Mediated Cytostatic and Angiostatic Effects
by Hirotetsu Takagi, Kosuke Kaji, Norihisa Nishimura, Koji Ishida, Hiroyuki Ogawa, Hiroaki Takaya, Hideto Kawaratani, Kei Moriya, Tadashi Namisaki, Takemi Akahane, Akira Mitoro and Hitoshi Yoshiji
Cells 2021, 10(3), 575; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030575 - 05 Mar 2021
Cited by 14 | Viewed by 3035
Abstract
Molecular targeted therapy with lenvatinib is commonly offered to advanced hepatocellular carcinoma (HCC) patients, although it is often interrupted by adverse effects which require a reduction in the initial dose. Thus, an alternative lenvatinib-based therapy to compensate for dose reduction is anticipated. This [...] Read more.
Molecular targeted therapy with lenvatinib is commonly offered to advanced hepatocellular carcinoma (HCC) patients, although it is often interrupted by adverse effects which require a reduction in the initial dose. Thus, an alternative lenvatinib-based therapy to compensate for dose reduction is anticipated. This study aimed to assess the effect of combination of low-dose of lenvatinib and the angiotensin-II (AT-II) receptor blocker losartan on human HCC cell growth. In vitro studies found that losartan suppressed the proliferation by inducing G1 arrest and caused apoptosis as indicated by the cleavage of caspase-3 in AT-II-stimulated HCC cell lines (Huh-7, HLE, and JHH-6). Losartan attenuated the AT-II-stimulated production of vascular endothelial growth factor-A (VEGF-A) and interleukin-8 and suppressed lenvatinib-mediated autocrine VEGF-A production in HCC cells. Moreover, it directly inhibited VEGF-mediated endothelial cell growth. Notably, the combination of lenvatinib and losartan augmented the cytostatic and angiostatic effects of the former at a low-dose, reaching those achieved with a conventional dose. Correspondingly, a HCC tumor xenograft assay showed that the oral administration of losartan combined with lenvatinib reduced the subcutaneous tumor burden and intratumor vascularization in BALB/c nude mice. These findings support that this regimen could be a viable option for patients intolerant to standard lenvatinib dosage. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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12 pages, 1410 KiB  
Article
Influence of Antihypertensive Treatment on RAAS Peptides in Newly Diagnosed Hypertensive Patients
by Annina S. Vischer, Gabriela M. Kuster, Raphael Twerenbold, Otmar Pfister, Qian Zhou, Andrea Villiger, Marko Poglitsch, Stephan Krähenbühl, Michael Mayr, Stefan Osswald, Manuel Haschke and Thilo Burkard
Cells 2021, 10(3), 534; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030534 - 03 Mar 2021
Cited by 6 | Viewed by 2263
Abstract
(1) Background: Recently, influences of antihypertensive treatment on the renin–angiotensin–aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1–7) as [...] Read more.
(1) Background: Recently, influences of antihypertensive treatment on the renin–angiotensin–aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1–7) as representers of two counter-regulatory axes. (2) Methods: In this randomized, open-label trial investigating RAAS peptides after the initiation of perindopril, olmesartan, amlodipine, or hydrochlorothiazide, Ang II and Ang (1–7) equilibrium concentrations were measured at 8 a.m. and 12 a.m. at baseline and after four weeks of treatment. Eighty patients were randomized (1:1:1:1 fashion). (3) Results: Between the four substances, we found significant differences regarding the concentrations of Ang II (p < 0.0005 for 8 a.m., 12 a.m.) and Ang (1–7) (p = 0.019 for 8 a.m., <0.0005 for 12 a.m.) four weeks after treatment start. Ang II was decreased by perindopril (p = 0.002), and increased by olmesartan (p < 0.0005), amlodipine (p = 0.012), and hydrochlorothiazide (p = 0.001). Ang (1–7) was increased by perindopril and olmesartan (p = 0.008/0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p = 0.317/ 0.109). (4) Conclusion: The initiation of all first line antihypertensive treatments causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptides shift upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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20 pages, 1727 KiB  
Article
Hyperglycemia Potentiates Prothrombotic Effect of Aldosterone in a Rat Arterial Thrombosis Model
by Anna Gromotowicz-Poplawska, Piotr Szoka, Agnieszka Zakrzeska, Patrycjusz Kolodziejczyk, Natalia Marcinczyk, Janusz Szemraj, Piotr Tutka and Ewa Chabielska
Cells 2021, 10(2), 471; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020471 - 22 Feb 2021
Cited by 2 | Viewed by 2413
Abstract
We investigated the role of aldosterone (ALDO) in the development of arterial thrombosis in streptozotocin-induced diabetic rats. To evaluate the effect of endogenous ALDO, the rats underwent adrenalectomy (ADX). ADX reduced the development of arterial thrombosis. A 1 h infusion of ALDO (30 [...] Read more.
We investigated the role of aldosterone (ALDO) in the development of arterial thrombosis in streptozotocin-induced diabetic rats. To evaluate the effect of endogenous ALDO, the rats underwent adrenalectomy (ADX). ADX reduced the development of arterial thrombosis. A 1 h infusion of ALDO (30 μg/kg/h) enhanced thrombosis in adrenalectomized rats, while this effect was potentiated in diabetic rats. ALDO shortened bleeding time, increased plasma levels of tissue factor (TF) and plasminogen activator inhibitor, decreased plasma level of nitric oxide (NO) metabolites, and increased oxidative stress. Moreover, 2 h incubation of human umbilical vein endothelial cells (HUVECs) with ALDO (10−7 M) disrupted hemostatic balance in endothelial cells in normoglycemia (glucose 5.5 mM), and this effect was more pronounced in hyperglycemia (glucose 30 mM). We demonstrated that the acute ALDO infusion enhances arterial thrombosis in rats and hyperglycemia potentiates this prothrombotic effect. The mechanism of ALDO action was partially mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors and related to impact of the hormone on primary hemostasis, TF-dependent coagulation cascade, fibrinolysis, NO bioavailability, and oxidative stress balance. Our in vitro study confirmed that ALDO induces prothrombotic phenotype in the endothelium, particularly under hyperglycemic conditions. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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16 pages, 2985 KiB  
Article
Cancer Stem Cells in Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma Express Components of the Renin-Angiotensin System
by Sam Siljee, Olivia Buchanan, Helen D. Brasch, Nicholas Bockett, Josie Patel, Erin Paterson, Gordon L. Purdie, Paul F. Davis, Tinte Itinteang and Swee T. Tan
Cells 2021, 10(2), 243; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020243 - 27 Jan 2021
Cited by 12 | Viewed by 3180
Abstract
We investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cell (CSC) subpopulations in metastatic head and neck cutaneous squamous cell carcinoma (mHNcSCC). Immunohistochemical staining demonstrated expression of prorenin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 [...] Read more.
We investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cell (CSC) subpopulations in metastatic head and neck cutaneous squamous cell carcinoma (mHNcSCC). Immunohistochemical staining demonstrated expression of prorenin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 (AT2R) in all cases and angiotensinogen in 14 cases; however, renin and ACE2 were not detected in any of the 20 mHNcSCC tissue samples. Western blotting showed protein expression of angiotensinogen in all six mHNcSCC tissue samples, but in none of the four mHNcSCC-derived primary cell lines, while PRR was detected in the four cell lines only. RT-qPCR confirmed transcripts of angiotensinogen, PRR, ACE, and angiotensin II receptor 1 (AT1R), but not renin or AT2R in all four mHNcSCC tissue samples and all four mHNcSCC-derived primary cell lines, while ACE2 was expressed in the tissue samples only. Double immunohistochemical staining on two of the mHNcSCC tissue samples showed expression of angiotensinogen by the SOX2+ CSCs within the tumor nests (TNs), and immunofluorescence showed expression of PRR and AT2R by the SOX2+ CSCs within the TNs and the peritumoral stroma (PTS). ACE was expressed on the endothelium of the tumor microvessels within the PTS. We demonstrated expression of angiotensinogen by CSCs within the TNs, PRR, and AT2R by the CSCs within the TNs and the PTS, in addition to ACE on the endothelium of tumor microvessels in mHNcSCC. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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16 pages, 2002 KiB  
Article
Central Administration of Angiotensin-(1-7) Improves Vasopressin Impairment and Hypotensive Response in Experimental Endotoxemia
by Patrícia Passaglia, Felipe de Lima Faim, Marcelo Eduardo Batalhão, Angelita Maria Stabile, Lusiane Maria Bendhack, José Antunes-Rodrigues, Riccardo Lacchini and Evelin Capellari Carnio
Cells 2021, 10(1), 105; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010105 - 08 Jan 2021
Cited by 6 | Viewed by 2285
Abstract
Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of [...] Read more.
Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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14 pages, 6055 KiB  
Article
SIRT3 Deficiency Sensitizes Angiotensin-II-Induced Renal Fibrosis
by Xiaomeng Feng, Han Su, Xiaochen He, Jian-Xiong Chen and Heng Zeng
Cells 2020, 9(11), 2510; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112510 - 20 Nov 2020
Cited by 24 | Viewed by 2704
Abstract
Background: Sirtuin 3 (SIRT3) has a crucial role in the cardiovascular diseases. Our previous study revealed that SIRT3 knockout (SIRT3KO) promoted cardiac pericyte–fibroblast transition. In this study, we investigated the involvement of pericyte and iron in angiotensin II (Ang-II)-mediated renal fibrosis in the [...] Read more.
Background: Sirtuin 3 (SIRT3) has a crucial role in the cardiovascular diseases. Our previous study revealed that SIRT3 knockout (SIRT3KO) promoted cardiac pericyte–fibroblast transition. In this study, we investigated the involvement of pericyte and iron in angiotensin II (Ang-II)-mediated renal fibrosis in the SIRT3KO mice. Methods and Results: NG2-DsRed mice and NG2-DsRed-SIRT3 knockout (SIRT3KO) mice were infused with saline or Ang-II (1000 ng/kg/min) for 4 weeks. Renal fibrosis, iron content and reactive oxygen species (ROS) were measured. Masson’s trichrome staining showed that SIRT3KO enhanced Ang-II-induced renal fibrosis. Immunostaining showed that Ang-II treatment increased the number of NG2-DsRed+ cells in the kidney, and SIRT3KO further enhanced NG2-DsRed+ cells. Moreover, SIRT3KO promoted pericyte differentiation into fibroblasts as evidenced by co-staining NG2-DsRed/FSP-1. Furthermore, DsRed/FSP-1+ and DsRed/transforming growth factor-β1 (TGF-β1)+ fibroblasts were elevated by SIRT3KO after Ang-II infusion. Ang-II-induced collagen I and TGF-β1 expression was also enhanced in the SIRT3KO mice. SIRT3KO significantly exacerbated Ang-II-induced iron accumulation. This was accompanied by an increase in acetyl-p53, HO-1 and FPN expression. Further, SIRT3KO sensitized Ang-II-induced upregulation of p47phox and gp91phox together with increased ROS formation in the kidney. Conclusion: Our study suggests that SIRT3 deficiency sensitized Ang-II-induced renal fibrosis by the mechanisms involved in promoting differentiation of pericytes into fibroblasts, exacerbating iron overload and accelerating NADPH oxidase-derived ROS formation. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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Review

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28 pages, 2490 KiB  
Review
Renin–Angiotensin–Aldosterone System and Immunomodulation: A State-of-the-Art Review
by Driss Laghlam, Mathieu Jozwiak and Lee S. Nguyen
Cells 2021, 10(7), 1767; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071767 - 13 Jul 2021
Cited by 38 | Viewed by 5708
Abstract
The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, [...] Read more.
The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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19 pages, 700 KiB  
Review
Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function
by Mariona Guitart-Mampel, Pedro Urquiza, Jordana I. Borges, Anastasios Lymperopoulos and Maria E. Solesio
Cells 2021, 10(6), 1552; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061552 - 19 Jun 2021
Cited by 12 | Viewed by 3161
Abstract
The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a [...] Read more.
The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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23 pages, 8202 KiB  
Review
The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis?
by Babak Saravi, Zhen Li, Corinna N. Lang, Bonaventura Schmid, Frauke K. Lang, Sibylle Grad, Mauro Alini, Robert Geoffrey Richards, Hagen Schmal, Norbert Südkamp and Gernot M. Lang
Cells 2021, 10(3), 650; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030650 - 15 Mar 2021
Cited by 30 | Viewed by 4735
Abstract
Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type [...] Read more.
Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1–7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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26 pages, 512 KiB  
Review
Angiotensin II and Angiotensin Receptors 1 and 2—Multifunctional System in Cells Biology, What Do We Know?
by Maksymilian Ziaja, Kinga Anna Urbanek, Karolina Kowalska and Agnieszka Wanda Piastowska-Ciesielska
Cells 2021, 10(2), 381; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020381 - 12 Feb 2021
Cited by 15 | Viewed by 3782
Abstract
For years, the renin-angiotensin system (RAS) has been perceived as a system whose role is to primarily modulate the functioning of the cardiovascular system. Years of research into the role of RAS have provided the necessary data to confirm that the role of [...] Read more.
For years, the renin-angiotensin system (RAS) has been perceived as a system whose role is to primarily modulate the functioning of the cardiovascular system. Years of research into the role of RAS have provided the necessary data to confirm that the role of RAS is very complex and not limited to the cardiovascular system. The presence of individual elements of the renin-angiotensin (RA) system allows to control many processes, ranging from the memorization to pro-cancer processes. Maintaining the proportions between the individual axes of the RA system allows for achieving a balance, often called homeostasis. Thus, any disturbance in the expression or activity of individual RAS elements leads to pathophysiological processes. Full article
(This article belongs to the Special Issue Renin–Angiotensin–Aldosterone System)
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