scholarly journals New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Anderson J. Ferreira ◽  
Tatiane M. Murça ◽  
Rodrigo A. Fraga-Silva ◽  
Carlos Henrique Castro ◽  
Mohan K. Raizada ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Therapeutic Strategies ◽  
Biologically Active ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
G Protein Coupled ◽  
Hydrolysis Of

Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). The discovery of the angiotensin-converting enzyme homologue ACE2 revealed important metabolic pathways involved in the Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation. Additionally, it is well established that the G protein-coupled receptor Mas is a functional ligand site for Ang-(1–7). The axis formed by ACE2/Ang-(1–7)/Mas represents an endogenous counter regulatory pathway within the RAS whose actions are opposite to the vasoconstrictor/proliferative arm of the RAS constituted by ACE/Ang II/AT1receptor. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and pulmonary system. Also, we will highlight the initiatives to develop potential therapeutic strategies based on this axis.

scholarly journals Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

2012 ◽  
Vol 216 (2) ◽  
pp. R1-R17 ◽  
Author(s):  
Robson A S Santos ◽  
Anderson J Ferreira ◽  
Thiago Verano-Braga ◽  
Michael Bader
Keyword(s):  
Renin Angiotensin System ◽  
Biologically Active ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Potential Interactions ◽  
G Protein Coupled

Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin–angiotensin system (RAS). Ang-(1–7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1–7). Thus, the axis formed by ACE2/Ang-(1–7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and AT1receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1–7) and Mas with AT1and AT2receptors.

scholarly journals Angiotensin Converting Enzyme 2, Angiotensin-(1-7), and Receptor Mas Axis in the Kidney

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Sergio Veloso Brant Pinheiro ◽  
Ana Cristina Simões e Silva
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Biological Effects ◽  
Renin Angiotensin System ◽  
Biologically Active ◽  
Renal Physiology ◽  
Dual Function ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
G Protein Coupled

In the past few years the understanding of the renin-angiotensin system (RAS) has improved, helping to better define the role of this system in physiological conditions and in human diseases. Besides Angiotensin (Ang) II, the biological importance of other Ang fragments was progressively evidenced. In this regard, Angiotensin- (Ang-) (1-7) was recognized as a biologically active product of the RAS cascade with a specific receptor, the G-protein-coupled receptor Mas, and that is mainly formed by the action of the angiotensin-converting enzyme (ACE) homolog enzyme, ACE2, which converts Ang II into Ang-(1-7). Taking into account the biological effects of these two mediators, Ang II and Ang-(1-7), the RAS can be envisioned as a dual function system in which the vasoconstrictor/proliferative or vasodilator/antiproliferative actions are primarily driven by the balance between Ang II and Ang-(1-7), respectively. In this paper, we will discuss our current understanding of the ACE2/Ang-(1-7)/Mas axis of the RAS in renal physiology and in the pathogenesis of primary hypertension and chronic kidney disease.

scholarly journals Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Chris Tikellis ◽  
M. C. Thomas
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Main Role ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Organ Protection ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Health And Disease

Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1–7 (Ang 1–7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1–7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection.

scholarly journals Dysregulation of ACE (Angiotensin-Converting Enzyme)-2 and Renin-Angiotensin Peptides in SARS-CoV-2 Mediated Mortality and End-Organ Injuries

Hypertension ◽  
2021 ◽  
Author(s):  
Kaiming Wang ◽  
Mahmoud Gheblawi ◽  
Anish Nikhanj ◽  
Matt Munan ◽  
Erika MacIntyre ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Tumor Necrosis Factor Receptor ◽  
Renin Angiotensin System ◽  
Adverse Outcomes ◽  
Blood Collection ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Angiotensin Peptides

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52–74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1–7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.

scholarly journals ACE2 the Janus-faced protein – from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19

2020 ◽  
Vol 134 (7) ◽  
pp. 747-750 ◽  
Author(s):  
Rhian M. Touyz ◽  
Hongliang Li ◽  
Christian Delles
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Basic Science ◽  
Physiological Role ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Sars Coronavirus ◽  
Multifunctional Protein ◽  
Angiotensin Converting Enzyme 2

Abstract Angiotensin converting enzyme 2 (ACE2) is the major enzyme responsible for conversion of Ang II into Ang-(1-7). It also acts as the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, which causes Coronavirus Disease (COVID)-19. In recognition of the importance of ACE2 and to celebrate 20 years since its discovery, the journal will publish a focused issue on the basic science and (patho)physiological role of this multifunctional protein.

scholarly journals Dual RAS blockade normalizes angiotensin-converting enzyme-2 expression and prevents hypertension and tubular apoptosis in Akita angiotensinogen-transgenic mice

2012 ◽  
Vol 302 (7) ◽  
pp. F840-F852 ◽  
Author(s):  
Chao-Sheng Lo ◽  
Fang Liu ◽  
Yixuan Shi ◽  
Hasna Maachi ◽  
Isabelle Chenier ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Gene And Protein Expression ◽  
Intrarenal Ras ◽  
Renal Proximal Tubular ◽  
The Right

We investigated the effects of dual renin-angiotensin system (RAS) blockade on angiotensin-converting enzyme-2 (Ace2) expression, hypertension, and renal proximal tubular cell (RPTC) apoptosis in type 1 diabetic Akita angiotensinogen (Agt)-transgenic (Tg) mice that specifically overexpress Agt in their RPTCs. Adult (11 wk old) male Akita and Akita Agt-Tg mice were treated with two RAS blockers (ANG II receptor type 1 blocker losartan, 30 mg·kg−1·day−1) and angiotensin-converting enzyme (ACE) inhibitor perindopril (4 mg·kg−1·day−1) in drinking water. Same-age non-Akita littermates and Agt-Tg mice served as controls. Blood pressure, blood glucose, and albuminuria were monitored weekly. The animals were euthanized at age 16 wk. The left kidneys were processed for immunohistochemistry and apoptosis studies. Renal proximal tubules were isolated from the right kidneys to assess gene and protein expression. Urinary ANG II and ANG 1–7 were quantified by ELISA. RAS blockade normalized renal Ace2 expression and urinary ANG 1–7 levels (both of which were low in untreated Akita and Akita Agt-Tg), prevented hypertension, albuminuria, tubulointerstitial fibrosis and tubular apoptosis, and inhibited profibrotic and proapoptotic gene expression in RPTCs of Akita and Akita Agt-Tg mice compared with non-Akita controls. Our results demonstrate the effectiveness of RAS blockade in preventing intrarenal RAS activation, hypertension, and nephropathy progression in diabetes and support the important role of intrarenal Ace2 expression in modulating hypertension and renal injury in diabetes.

scholarly journals The ANG-(1–7)/ACE2/mas axis in the regulation of nephron function

2010 ◽  
Vol 298 (6) ◽  
pp. F1297-F1305 ◽  
Author(s):  
Carlos M. Ferrario ◽  
Jasmina Varagic
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Therapeutic Interventions ◽  
Experimental Hypertension ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
A Site

The study of experimental hypertension and the development of drugs with selective inhibitory effects on the enzymes and receptors constituting the components of the circulating and tissue renin-angiotensin systems have led to newer concepts of how this system participates in both physiology and pathology. Over the last decade, a renewed emphasis on understanding the role of angiotensin-(1–7) and angiotensin-converting enzyme 2 in the regulation of blood pressure and renal function has shed new light on the complexity of the mechanisms by which these components of the renin angiotensin system act in the heart and in the kidneys to exert a negative regulatory influence on angiotensin converting enzyme and angiotensin II. The vasodepressor axis composed of angiotensin-(1–7)/angiotensin-converting enzyme 2/mas receptor emerges as a site for therapeutic interventions within the renin-angiotensin system. This review summarizes the evolving knowledge of the counterregulatory arm of the renin-angiotensin system in the control of nephron function and renal disease.

The role of angiotensin converting enzyme 2 in the generation of angiotensin 1–7 by rat proximal tubules

2005 ◽  
Vol 288 (2) ◽  
pp. F353-F362 ◽  
Author(s):  
Ningjun Li ◽  
Joseph Zimpelmann ◽  
Keding Cheng ◽  
John A. Wilkins ◽  
Kevin D. Burns
Keyword(s):  
Rat Kidney ◽  
Biologically Active ◽  
Relative Distribution ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Nephron Segments ◽  
Luminal Perfusion ◽  
Proximal Tubular

ANG converting enzyme (ACE) 2 (ACE2) is a homologue of ACE, which is not blocked by conventional ACE inhibitors. ACE2 converts ANG 1–10 (ANG I) to ANG 1–9, which can be hydrolyzed by ACE to form the biologically active peptide ANG 1–7. ACE2 is expressed in the kidney, but its precise intrarenal localization is unclear, and the role of intrarenal ACE2 in the production of ANG 1–7 is unknown. The present studies determined the relative distribution of ACE2 in the rat kidney and defined its role in the generation of ANG 1–7 in proximal tubule. In microdissected rat nephron segments, semiquantitative RT-PCR revealed that ACE2 mRNA was widely expressed, with relatively high levels in proximal straight tubule (PST). Immunohistochemistry demonstrated ACE2 protein in tubular segments, glomeruli, and endothelial cells. Utilizing mass spectrometry, incubation of isolated PSTs with ANG I (10−6 M) led to generation of ANG 1–7 (sensitivity of detection > 1 × 10−9 M), accompanied by the formation of ANG 1–8 (ANG II) and ANG 1–9. The ACE2 inhibitor DX600 completely blocked ANG I-mediated generation of ANG 1–7. Incubation of PSTs with ANG 1–9 also led to generation of ANG 1–7, an effect blocked by the ACE inhibitor captopril or enalaprilat, but not by DX600. Incubation of PSTs with ANG II or luminal perfusion of ANG II did not result in detection of ANG 1–7. The results indicate that ACE2 is widely expressed in rat nephron segments and contributes to the production of ANG 1–7 from ANG I in PST. ANG II may not be a major substrate for ACE2 in isolated PST. The data suggest that ACE2-mediated production of ANG 1–7 represents an important component of the proximal tubular renin-ANG system.

scholarly journals Gastrointestinal and kidney manifestations in SARS-CoV and SARS-CoV-2 infections: role of angiotensin-converting enzyme 2

2020 ◽  
Vol 25 (1) ◽  
pp. 7-20
Author(s):  
Fatemeh Maghool ◽  
◽  
Mohammad Hassan Emami ◽  
Samaneh Mohammadzadeh ◽  
Aida Heidari ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Gastrointestinal Symptoms ◽  
Renin Angiotensin System ◽  
Structural Similarity ◽  
Clinical Feature ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Kidney Impairment

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 2020, which has a substantial structural similarity to severe acute respiratory syndrome coronavirus (SARS-CoV) that caused the outbreak in 2003, is currently a threat to global health. Lung involvement is the principal clinical feature in infected patients but extra-pulmonary clinical presentations are also common. The reasons for the extensive involvement of other organs are not yet clear. Angiotensin-converting enzyme 2 (ACE2), the key peptide of renin–angiotensin system (RAS), has recently identified as a major receptor for the both SARS-CoV and SARS-CoV-2 that might be a main target of coronavirus infection. ACE2 is mainly expressed in the pulmonary pneumocytes, the small intestine enterocytes as well as the proximal tubule epithelial cells of the kidneys. In addition to the respiratory tract infection symptoms, the noticeable prevalence of gastrointestinal symptoms as well as kidney impairment in hospitalized infected patients highlights other routes of infection/transmission. In present review, we discussed the role of RAS with emphasis on ACE2 in the pathogenesis of SARS-CoV and SARS-CoV-2, particularly in gastrointestinal and kidney manifestations of the diseases.

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