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Journal of the... 2022Renin-angiotensin system (RAS), as a critical system for controlling body fluid and hemostasis, contains peptides and receptors, including angiotensin 1-7 (Ang 1-7) and... (Review)
Review
Renin-angiotensin system (RAS), as a critical system for controlling body fluid and hemostasis, contains peptides and receptors, including angiotensin 1-7 (Ang 1-7) and Mas receptor (MasR). Ang 1-7 implements its function via MasR. Ang II is another peptide in RAS that performs its actions via two Ang II type 1 and 2 receptors (AT1R and AT2R). The functions of AT2R and MasR are very similar, and both have a vasodilation effect, while AT1R has a vasoconstriction role. MasR affects many mechanisms in the brain, heart, blood vessels, kidney, lung, endocrine, reproductive, skeletal muscle, and liver and probably acts like a paracrine hormone in these organs. The effect of Ang 1-7 in the kidney is complex according to the hydroelectrolyte status, the renal sympathetic nervous system, and the activity level of the RAS. The MasR expression and function seem more complex than Ang II receptors and have interacted with Ang II receptors and many other factors, including sex hormones. Also, pathological conditions including hypertension, diabetes, and ischemia-reperfusion could change MasR expression and function. In this review, we consider the role of sex differences in MasR expression and functions in the renal system under physiological and pathological conditions.
Topics: Angiotensin I; Angiotensin II; Female; Humans; Male; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Sex Characteristics
PubMed: 36148474
DOI: 10.1155/2022/1327839 -
Reviews in Cardiovascular Medicine Sep 2021The renin-angiotensin system (RAS) helps to regulate cardiovascular function, the maintenance of electrolyte and fluid balance, and blood pressure. The RAS contains two... (Review)
Review
The renin-angiotensin system (RAS) helps to regulate cardiovascular function, the maintenance of electrolyte and fluid balance, and blood pressure. The RAS contains two axes; the angiotensin-converting enzyme/angiotensin II/Ang II type 1 receptors (ACE/Ang II/AT) classic axis, which has a role in regulating blood pressure, vascular oxidative stress, coagulation, and cellular proliferation. The other is the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptors (ACE2/Ang-(1-7)/Mas) axis, which can inhibit the former axis, improve fat metabolism, reduce inflammation and oxidative stress, and enhance glucose tolerance and insulin sensitivity. The ACE2/Ang-(1-7)/Mas axis is found in blood vessels, kidneys, liver, pancreas and the brain. It can protect the body from abnormalities in glucose metabolism. The ACE2/Ang-(1-7)/Mas axis can enhance glucose tolerance and improve insulin sensitivity by protecting pancreatic β cells, increasing insulin secretion, improving glucose metabolism in adipose tissue, enhancing glucose uptake by skeletal muscle, and inhibiting hepatic gluconeogenesis. This article reviews the main characteristics and functions of the ACE2/Ang-(1-7)/Mas axis and its regulation of glucose metabolism in order to demonstrate its potential as a target for the treatment of metabolic diseases such as diabetes.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Glucose; Humans; Peptide Fragments
PubMed: 34565075
DOI: 10.31083/j.rcm2203083 -
Pflugers Archiv : European Journal of... Mar 2023The renal renin-angiotensin system (RAS) is involved in the development of chronic kidney disease. Here, we investigated whether mice with reduced renal angiotensin...
The renal renin-angiotensin system (RAS) is involved in the development of chronic kidney disease. Here, we investigated whether mice with reduced renal angiotensin I-converting enzyme (ACE) are protected against aristolochic acid nephropathy (AAN). To further elucidate potential molecular mechanisms, we assessed the renal abundances of several major RAS components. AAN was induced using aristolochic acid I (AAI). Glomerular filtration rate (GFR) was determined using inulin clearance and renal protein abundances of renin, angiotensinogen, angiotensin I-converting enzyme (ACE) 2, and Mas receptor (Mas) were determined in ACE and C57BL/6J control mice by Western blot analyses. Renal ACE activity was determined using a colorimetric assay and renal angiotensin (Ang) (1-7) concentration was determined by ELISA. GFR was similar in vehicle-treated mice of both strains. AAI decreased GFR in controls but not in ACE mice. Furthermore, AAI decreased renal ACE activity in controls but not in ACE mice. Vehicle-treated ACE mice had significantly higher renal ACE2 and Mas protein abundances than controls. AAI decreased renal ACE2 protein abundance in both strains. Furthermore, AAI increased renal Mas protein abundance, although the latter effect did not reach statistical significance in the ACE mice. Renal Ang(1-7) concentration was similar in vehicle-treated mice of both strains. AAI increased renal Ang(1-7) concentration in the ACE mice but not in the controls. Mice with reduced renal ACE are protected against AAN. Our data suggest that in the face of renal ACE deficiency, AAI may activate the ACE2/Ang(1-7)/Mas axis, which in turn may deploy its reno-protective effects.
Topics: Mice; Animals; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Angiotensin-Converting Enzyme 2; Angiotensin II; Mice, Inbred C57BL; Renin-Angiotensin System; Renal Insufficiency, Chronic; Angiotensin I; Peptide Fragments
PubMed: 36520238
DOI: 10.1007/s00424-022-02779-4 -
Biomedicine & Pharmacotherapy =... Jan 2019Local renin-angiotensin system (RAS) in the pancreas is linked to the modulation of glucose-stimulated insulin secretion (GSIS) in beta cells and insulin sensitivity in... (Review)
Review
Local renin-angiotensin system (RAS) in the pancreas is linked to the modulation of glucose-stimulated insulin secretion (GSIS) in beta cells and insulin sensitivity in target tissues, emerging as a promising tool in the prevention and/or treatment of obesity, diabetes, and systemic arterial hypertension. Insulin resistance alters pancreatic islet cell distribution and morphology and hypertrophied islets exhibit upregulated angiotensin II type 1 receptor, which drives oxidative stress, apoptosis, and fibrosis, configuring beta cell dysfunction and diminishing islet lifespan. Pharmacological modulation of RAS has shown beneficial effects in diet-induced obesity model, mainly related to the translational potential that angiotensin receptor blockers and ECA2/ANG (1-7)/MAS receptor axis modulation have when it comes to islet preservation and type 2 diabetes prevention and/or treatment. This review describes the existing evidence for different approaches to blocking RAS elements in the management of insulin resistance and diabetes and focuses on islet remodeling and GSIS in rodents and humans.
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Drug Delivery Systems; Homeostasis; Humans; Insulin Resistance; Islets of Langerhans; Peptide Fragments; Renin-Angiotensin System
PubMed: 30404071
DOI: 10.1016/j.biopha.2018.10.191 -
Journal of the... 2018Hyperglycemia decreases angiotensin-(1-7), the endogenous counter-regulator of angiotensin II in the retina.
HYPOTHESIS
Hyperglycemia decreases angiotensin-(1-7), the endogenous counter-regulator of angiotensin II in the retina.
MATERIALS AND METHODS
The distribution and levels of retinal angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)) were evaluated by confocal imaging and quantitative immunohistochemistry during the development of streptozotocin-induced diabetes in rats.
RESULTS
In the nondiabetic eye, Ang II was localized to the endfeet of Müller cells, extending into the cellular processes of the inner plexiform layer and inner nuclear layer; Ang-(1-7) showed a wider distribution, extending from the foot plates of the Müller cells to the photoreceptor layer. Eyes from diabetic animals showed a higher intensity and extent of Ang II staining compared with nondiabetic eyes, but lower intensity with a reduced distribution of Ang-(1-7) immunoreactivity. Treatment of the diabetic animals with the angiotensin-converting enzyme inhibitor (ACEI) captopril showed a reduced intensity of Ang II staining, whereas increased intensity and distribution were evident with Ang-(1-7) staining.
CONCLUSIONS
These studies reveal that pharmacological inhibition with ACEIs may provide a specific intervention for the management of the diabetes-induced decline in retinal function, reversing the profile of the endogenous angiotensin peptides closer to the normal condition.
Topics: Angiotensin I; Angiotensin II; Animals; Blood Glucose; Body Weight; Captopril; Diabetes Mellitus, Experimental; Female; Hyperglycemia; Peptide Fragments; Rats, Sprague-Dawley; Retina
PubMed: 30126320
DOI: 10.1177/1470320318789323 -
Molecules (Basel, Switzerland) Mar 2022The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2),... (Review)
Review
The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its downregulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.
Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Humans; Receptor, Angiotensin, Type 1; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35408447
DOI: 10.3390/molecules27072048 -
The European Respiratory Journal Jul 2020In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory,...
BACKGROUND
In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1-7) axis in human PAH is incompletely understood.
METHODS
We studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1-7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1-9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically.
RESULTS
Of the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72-1.88 pmol·mL 0.19, 0.10-0.37 pmol·mL; p<0.001) and of aldosterone (88.7, 58.7-132 ng·dL 12.9, 9.55-19.9 ng·dL; p<0.001). Conversely, PAH patients had a lower concentration of Ang(1-7) than controls (0.69, 0.474-0.91 pmol·mL 4.07, 2.82-6.73 pmol·mL; p<0.001), and a lower concentration of Ang(1-9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35-13.2 ng·mL 4.53, 1.47-14.3 ng·mL; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08-2.81 nmol·mL 5.97, 3.1-17.8 nmol·mL; p<0.001). No significant differences were found among the three different aetiological forms of PAH.
CONCLUSIONS
The AngII-ACE2-Ang(1-7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Humans; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Arterial Hypertension
PubMed: 32241831
DOI: 10.1183/13993003.02416-2019 -
Molecular Human Reproduction Jun 2020The 2019 novel coronavirus (2019-nCoV) appeared in December 2019 and then spread throughout the world rapidly. The virus invades the target cell by binding to... (Review)
Review
The 2019 novel coronavirus (2019-nCoV) appeared in December 2019 and then spread throughout the world rapidly. The virus invades the target cell by binding to angiotensin-converting enzyme (ACE) 2 and modulates the expression of ACE2 in host cells. ACE2, a pivotal component of the renin-angiotensin system, exerts its physiological functions by modulating the levels of angiotensin II (Ang II) and Ang-(1-7). We reviewed the literature that reported the distribution and function of ACE2 in the female reproductive system, hoping to clarify the potential harm of 2019-nCoV to female fertility. The available evidence suggests that ACE2 is widely expressed in the ovary, uterus, vagina and placenta. Therefore, we believe that apart from droplets and contact transmission, the possibility of mother-to-child and sexual transmission also exists. Ang II, ACE2 and Ang-(1-7) regulate follicle development and ovulation, modulate luteal angiogenesis and degeneration, and also influence the regular changes in endometrial tissue and embryo development. Taking these functions into account, 2019-nCoV may disturb the female reproductive functions through regulating ACE2.
Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Betacoronavirus; COVID-19; Coronavirus Infections; Female; Gene Expression Regulation; Genitalia, Female; Host-Pathogen Interactions; Humans; Pandemics; Peptide Fragments; Peptidyl-Dipeptidase A; Pneumonia, Viral; Pregnancy; Protein Binding; Receptors, Virus; Renin-Angiotensin System; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 32365180
DOI: 10.1093/molehr/gaaa030 -
Molecular Biology Reports May 2021Angiotensin-converting enzyme (ACE, EC 3.4.15.1) in the renin-angiotensin system regulates blood pressure by catalyzing angiotensin I to the vasoconstrictor angiotensin...
Angiotensin-converting enzyme (ACE, EC 3.4.15.1) in the renin-angiotensin system regulates blood pressure by catalyzing angiotensin I to the vasoconstrictor angiotensin II. In this study, the ACE was purified and characterized from sheep lung. The kinetic properties of the ACE were designated. The inhibition effect of captopril, a specific ACE inhibitor, was determined. ACE was purified from sheep lung using the affinity chromatography method in one step. NHS-activated Sepharose 4 Fast Flow as column filler and lisinopril as a ligand in this method used. The molecular weight and purity of ACE were designated using the SDS-PAGE method. Optimum temperature and optimum pH were found for purified ACE. K and V values from Lineweaver-Burk charts determined. The inhibition type, IC, and K values of captopril on purified ACE were identified. ACE was 6405-fold purified from sheep lung by affinity chromatography in one step and specific activity was 16871 EU/mg protein. The purity and molecular weight of ACE were found with SDS-PAGE and observed two bands at around 60 kDa and 70 kDa on the gel. Optimum temperature and optimum pH were designated for purified ACE. Optimum temperature and pH were found as 40 °C and pH 7.4, respectively. V and K values were calculated to be 35.59 (µmol/min).mL and 0.18 mM, respectively. IC value of captopril was found as 0.51 nM. The inhibition type of captopril was determined as non-competitive from the Lineweaver-Burk graph and the K value was 0.39 nM. As a result, it was observed in this study that the ACE enzyme can be successfully purified from sheep lungs in one step. Also, it was determined that captopril, which is a specific ACE inhibitor, has a significant inhibitory effect with a very low IC value of 0.51 nM.
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Chromatography, Affinity; Electrophoresis, Polyacrylamide Gel; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Kinetics; Lisinopril; Lung; Molecular Weight; Peptidyl-Dipeptidase A; Sheep; Temperature
PubMed: 34086160
DOI: 10.1007/s11033-021-06432-8 -
Biochemical Pharmacology Feb 2023Cardiovascular disease is the major cause of mortality and disability, with hypertension being the most prevalent risk factor. Excessive activation of the... (Review)
Review
Cardiovascular disease is the major cause of mortality and disability, with hypertension being the most prevalent risk factor. Excessive activation of the renin-angiotensin system (RAS) under pathological conditions, leading to vascular remodeling and inflammation, is closely related to cardiovascular dysfunction. The counter-regulatory axis of the RAS consists of angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7), angiotensin (1-9), alamandine, proto-oncogene Mas receptor, angiotensin II type-2 receptor and Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the overactivated RAS. In this review, we summarize the latest insights into the complexity and interplay of the counter-regulatory RAS axis in hypertension, highlight the pathophysiological functions of ACE2, a multifunctional molecule linking hypertension and COVID-19, and discuss the function and therapeutic potential of targeting this counter-regulatory RAS axis to prevent and treat hypertension in the context of the current COVID-19 pandemic.
Topics: Humans; Angiotensin I; Angiotensin-Converting Enzyme 2; COVID-19; Hypertension; Pandemics; Peptide Fragments; Receptors, G-Protein-Coupled; Renin-Angiotensin System
PubMed: 36481346
DOI: 10.1016/j.bcp.2022.115370