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Advances in the Renin-Angiotensin System
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Advances in the Renin-Angiotensin System

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 6185

Special Issue Editor

Dr. Alexis A. Gonzalez

E-Mail Website
Guest Editor
Institute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, Chile
Interests: renal system; renal injury; arterial hypertension; renal dysfunction; renin–angiotensin system
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The renin–angiotensin system (RAS) plays a crucial role in the regulation of blood pressure, sodium handling, volume balance and in organ damage during its inappropriate activation. RAS overactivation directly contributes to the establishment of hypertension and cardiovascular diseases. However, recent evidence demonstrates an important role of RAS in metabolic disorders, diabetic disease, compensatory alterations in pregnancy, neurodegenerative disorders, among others. The study of the physiology and pathophysiology of RAS could bring new insights that enable a better comprehension of the mechanisms responsible for its regulation and interactions with signaling pathways, all of which may allow the development of new pharmacological targets.

Dr. Alexis A. Gonzalez
Guest Editor

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Keywords

  • renin–angiotensin system (RAS)
  • renin
  • angiotensin
  • angiotensin receptor
  • new therapeutic target
  • RAS and hypertension
  • RAS and cardiovascular diseases

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Related Special Issue

Published Papers (5 papers)

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Research

13 pages, 1466 KiB  
Article
Diagnostic Accuracy of Aldosterone and Renin Measurement by Chemiluminescence for Screening of Patients with Primary Aldosteronism
by Martina Tetti, Jacopo Burrello, Jessica Goi, Mirko Parasiliti-Caprino, Giulia Gioiello, Fabio Settanni, Silvia Monticone, Paolo Mulatero and Giulio Mengozzi
Int. J. Mol. Sci. 2024, 25(15), 8453; https://doi.org/10.3390/ijms25158453 - 2 Aug 2024
Viewed by 787
Abstract
Primary aldosteronism (PA) is the most common cause of endocrine arterial hypertension, and the suggested screening test for case detection is the aldosterone-to-renin ratio (ARR) or aldosterone-to-direct renin ratio (ADRR) based on radio-immunoassay (RIA) and chemiluminescence assay (CLIA), respectively. The objective of our [...] Read more.
Primary aldosteronism (PA) is the most common cause of endocrine arterial hypertension, and the suggested screening test for case detection is the aldosterone-to-renin ratio (ARR) or aldosterone-to-direct renin ratio (ADRR) based on radio-immunoassay (RIA) and chemiluminescence assay (CLIA), respectively. The objective of our study was to evaluate the reliability of CLIA for aldosterone and renin measurement and the diagnostic performance of ADRR. A prospective cohort of 1110 patients referred to a single laboratory medicine center underwent measurement of aldosterone and direct renin concentration (DRC) by CLIA and measurement of aldosterone and plasma renin activity (PRA) by RIA. Of 1110 patients, 640 obtained a final diagnosis of hypertension, and 90 of these patients were diagnosed with PA. Overall, between-method correlation was highly significant for aldosterone concentrations (R = 0.945, p < 0.001) and less strong but significant for DRC/PRA (R = 0.422, p < 0.001). Among hypertensive patients, in PA cases, the areas under the receiver operator characteristics (ROC) curves were 0.928 (95% confidence interval 0.904–0.954) for ADRR and 0.943 (95% confidence interval 0.920–0.966) for ARR and were comparable and not significantly different. The highest accuracy was obtained with an ADRR cut-off of 25 (ng/L)/(mIU/L), displaying a sensitivity of 91% and a specificity of 85%. The chemiluminescence assay for aldosterone and DRC is a reliable method for PA diagnosis compared to the classical RIA method. Full article
(This article belongs to the Special Issue Advances in the Renin-Angiotensin System)
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17 pages, 2953 KiB  
Article
SARS-CoV-2 Spike Protein Enhances Carboxypeptidase Activity of Angiotensin-Converting Enzyme 2
by Xóchitl Andrea Mendiola-Salazar, Melanie A. Munguía-Laguna, Martha Franco, Agustina Cano-Martínez, José Santamaría Sosa and Rocío Bautista-Pérez
Int. J. Mol. Sci. 2024, 25(11), 6276; https://doi.org/10.3390/ijms25116276 - 6 Jun 2024
Cited by 1 | Viewed by 1201
Abstract
In this study, we investigated whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein may modify angiotensin-converting enzyme 2 (ACE2) activity in the plasma, heart, kidney, liver, lung, and six brain regions (amygdala, brain stem, cortex, hippocampus, hypothalamus, and striatum) of diabetic and [...] Read more.
In this study, we investigated whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein may modify angiotensin-converting enzyme 2 (ACE2) activity in the plasma, heart, kidney, liver, lung, and six brain regions (amygdala, brain stem, cortex, hippocampus, hypothalamus, and striatum) of diabetic and hypertensive rats. We determine ACE2 activity in the plasma and lysates of heart, kidney, liver, lung, and six brain regions. MLN-4760 inhibits ACE2 activity in the plasma and all organs. On the other hand, soluble ACE2 (sACE2) activity increased in the plasma of diabetic rats, and there was no change in the plasma of hypertensive rats. ACE2 activity was augmented in the liver, brain stem, and striatum, while it decreased in the kidney, amygdala, cortex, and hippocampus of diabetic rats. ACE2 activity increased in the kidney, liver, and lung, while it decreased in the heart, amygdala, cortex, and hypothalamus of hypertensive rats. We measured the ACE2 content via enzyme-linked immunosorbent assay and found that ACE2 protein levels increased in the heart, while it decreased in the plasma, kidney, brain stem, cortex, hippocampus, hypothalamus, and striatum of diabetic rats. ACE2 protein levels decreased in the brain stem, cortex, hippocampus, and hypothalamus of hypertensive rats. Our data showed that the spike protein enhanced ACE2 activity in the liver and lungs of diabetic rats, as well as in the heart and three of the brain regions (cortex, hypothalamus, and striatum) of hypertensive rats. Full article
(This article belongs to the Special Issue Advances in the Renin-Angiotensin System)
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11 pages, 963 KiB  
Article
Urinary Angiotensinogen Displays Sexual Dimorphism in Non-Diabetic Humans and Mice with Overweight
by Alexis A. Gonzalez, Bruna Visniauskas, Virginia Reverte, Ventaka N. Sure, Zoe Vallotton, Bryan S. Torres, Marco A. Acosta, Mahlet Zemedkun, Prasad V. Katakam and Minolfa C. Prieto
Int. J. Mol. Sci. 2024, 25(1), 635; https://doi.org/10.3390/ijms25010635 - 4 Jan 2024
Cited by 1 | Viewed by 1373
Abstract
Increased body weight (BW) induces inappropriate renin–angiotensin system (RAS) activation. The activation of the intrarenal RAS is associated with increased urinary angiotensinogen (uAGT), blood pressure (BP), and kidney damage. Here, we examined uAGT excretion levels in young non-diabetic human subjects with overweight (OW) [...] Read more.
Increased body weight (BW) induces inappropriate renin–angiotensin system (RAS) activation. The activation of the intrarenal RAS is associated with increased urinary angiotensinogen (uAGT), blood pressure (BP), and kidney damage. Here, we examined uAGT excretion levels in young non-diabetic human subjects with overweight (OW) and non-diabetic mice with high-fat diet (HFD)-induced OW. Human subjects (women and men; 20–28 years old) included two groups: (a) overweight (OW, n = 17, BMI ≥ 25); and (b) controls (normal weight (NW; n = 26, BMI ≤ 25). In these subjects, we measured BP, albuminuria, and protein levels of uAGT by ELISA adjusted by urinary creatinine (expressed by uAGT/uCrea). Mice (female and male C57BL/6J mice, 8 ± 2 weeks of age) also included two groups: HFD or normal fat diet (NFD) fed for 8 weeks. We measured BW, fasting blood glucose (FBG), BP by telemetry, albuminuria, and uAGT by ELISA. In humans: (i) no significant changes were observed in BP, albuminuria, and FBG when comparing NW and OW subjects; (ii) multivariate logistic regression analysis of independent predictors related to uAGT/uCrea levels demonstrated a strong association between uAGT and overweight; (iii) urinary reactive oxygen species (ROS) were augmented in men and women with OW; (iv) the uAGT/uCrea ratio was higher in men with OW. However, the uAGT/uCrea values were lower in women even with OW. In mice: (i) males fed an HFD for 8 weeks became OW while females did not; (ii) no changes were observed either in FBG, BP, or albuminuria; (iii) kidney ROS were augmented in OW male mice after 28 weeks but not in females; (iv) OW male mice showed augmented excretion of uAGT but this was undetectable in females fed either NFD or HFD. In humans and mice who are OW, the urinary excretion of AGT differs between males and females and overcomes overt albuminuria. Full article
(This article belongs to the Special Issue Advances in the Renin-Angiotensin System)
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Graphical abstract

18 pages, 12102 KiB  
Article
Myocardial Angiotensin-Converting Enzyme 2 Protein Expression in Ischemic Heart Failure
by Vitalija Siratavičiūtė, Dalia Pangonytė, Lina Utkienė, Lina Jusienė, Jolanta Marcinkevičienė, Zita Stanionienė and Reda Radikė
Int. J. Mol. Sci. 2023, 24(24), 17145; https://doi.org/10.3390/ijms242417145 - 5 Dec 2023
Viewed by 1135
Abstract
The angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis plays a significant role in regulating myocardial remodeling and the development of heart failure (HF), with ACE2 being the primary focus. However, contemporary understanding of the membrane-bound form of the human ACE2 protein remains insufficient. The [...] Read more.
The angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis plays a significant role in regulating myocardial remodeling and the development of heart failure (HF), with ACE2 being the primary focus. However, contemporary understanding of the membrane-bound form of the human ACE2 protein remains insufficient. The purpose of this study was to determine the expression of ACE2 protein in different cells of the left ventricular myocardium in non-diseased hearts and at various stages of ischemic HF. A total of 103 myocardial tissue samples from the left ventricle underwent quantitative and semi-quantitative immunohistochemical analysis. Upon assessing ACE2 immunostaining in all myocardial cells through unselective digital image analysis, there was no change in the stage A HF group. Nevertheless, the expression of ACE2 membrane protein in cardiomyocytes showed a tendency to increase, while non-cardiomyocyte ACE2 expression decreased significantly (p < 0.001). In the stage B HF group, the intensity of ACE2 immunostaining continued to increase with rising cardiomyocyte ACE2 expression (p < 0.001). Non-cardiomyocyte expression, in contrast, remained similar to that observed in the stage A HF group. In the stages C/D HF group, ACE2 expression reached its highest level in cardiomyocytes (p < 0.001), while ACE2 expression in non-cardiomyocytes was the lowest (p < 0.001). These changes in ACE2 protein levels are associated with left ventricular remodeling in ischemic HF. Full article
(This article belongs to the Special Issue Advances in the Renin-Angiotensin System)
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9 pages, 1344 KiB  
Communication
Acute In Vivo Administration of Compound 21 Stimulates Akt and ERK1/2 Phosphorylation in Mouse Heart and Adipose Tissue
by Diego T. Quiroga, Jorge A. Narvaéz Pardo, María G. Zubiría, Benjamín Barrales, Marina C. Muñoz, Andrés Giovambattista and Fernando P. Dominici
Int. J. Mol. Sci. 2023, 24(23), 16839; https://doi.org/10.3390/ijms242316839 - 28 Nov 2023
Cited by 1 | Viewed by 1098
Abstract
The angiotensin II type 2 (AT2) receptor has a role in promoting insulin sensitivity. However, the mechanisms underlying the AT2 receptor-induced facilitation of insulin are still not completely understood. Therefore, we investigated whether acute in vivo administration of AT2 [...] Read more.
The angiotensin II type 2 (AT2) receptor has a role in promoting insulin sensitivity. However, the mechanisms underlying the AT2 receptor-induced facilitation of insulin are still not completely understood. Therefore, we investigated whether acute in vivo administration of AT2 receptor agonist compound 21 (C21) could activate insulin signaling molecules in insulin-target tissues. We report that, in male C57BL/6 mice, an acute (5 min, 0.25 mg/kg; i.v.) injection of C21 induces the phosphorylation of Akt and ERK1/2 at activating residues (Ser473 and Thr202/Tyr204, respectively) in both epididymal white adipose tissue (WAT) and heart tissue. In WAT, the extent of phosphorylation (p) of Akt and ERK1/2 induced by C21 was approximately 65% of the level detected after a bolus injection of a dose of insulin known to induce maximal activation of the insulin receptor (IR). In the heart, C21 stimulated p-Akt to a lesser extent than in WAT and stimulated p-ERK1/2 to similar levels to those attained by insulin administration. C21 did not modify p-IR levels in either tissue. We conclude that in vivo injection of the AT2 receptor agonist C21 activates Akt and ERK1/2 through a mechanism that does not involve the IR, indicating the participation of these enzymes in AT2R-mediated signaling. Full article
(This article belongs to the Special Issue Advances in the Renin-Angiotensin System)
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