Immunolocalization of angiotensin-(1-7), angiotensin II and angiotensin-converting enzyme 2 in goat ovary

There is increasing evidence as to the participation of the ovarian renin-angiotensin system in important reproductive processes. The inhibition of the angiotensin-converting enzyme (ACE) caused an increase in the rate of ovulation and pregnancy in the artificial insemination protocol has fixed time (TFIA). This study aimed to investigate the presence and location of Ang II, Ang- (1-7) and ACE2 in goat ovaries and the possibility of the involvement of these peptides in previous results. Ten ovaries from goats were collected in a slaughterhouse, washed in buffered PBS, perfused with protease inhibitor solution and processed for immunohistochemistry protocol. The search for peptides was performed using the avidin–biotin–peroxidase method. A strong immunoreactivity for Ang II in theca cells of antral follicles and corpus luteum was observed. Antral follicles (theca cells), corpus luteum and oocyte cytoplasm in early antral follicles exhibited strong immunoreactivity for Ang-(1-7). There was strong immunoreactivity for ACE2 in the cytoplasm of luteal cells and theca cells of antral follicles. In this study, for the first time, the presence and location of Ang II, Ang-(1-7) and ACE2 are reported in goat ovary, suggesting that there is participation in follicular development, oocyte maturation and corpus luteum development.

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

Hypertension ◽

10.1161/hypertensionaha.121.18295 ◽

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.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00340.2011 ◽

2012 ◽

Vol 302 (7) ◽

pp. F840-F852 ◽

Cited By ~ 39

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.

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Chymase-dependent production of angiotensin II: an old enzyme in old hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00534.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. H223-H231 ◽

Cited By ~ 17

Author(s):

Ghezal Froogh ◽

John T. Pinto ◽

Yicong Le ◽

Sharath Kandhi ◽

Yeabsra Aleligne ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Renin Angiotensin System ◽

Ang Ii ◽

Aged Rats ◽

Converting Enzyme ◽

Local Formation ◽

Angiotensin System ◽

Renin Angiotensin ◽

Age Dependent

Age-dependent alteration of the renin-angiotensin system (RAS) and generation of angiotensin II (Ang II) are well documented. By contrast, RAS-independent generation of Ang II in aging and its responses to exercise have not been explored. To this end, we examined the effects of chymase, a secretory serine protease, on the angiotensin-converting enzyme (ACE)-independent conversion of Ang I to Ang II. We hypothesized that age-dependent alteration of cardiac Ang II formation is chymase dependent in nature and is prevented by exercise training. Experiments were conducted on hearts isolated from young (3 mo), aged sedentary (24 mo), and aged rats chronically exercised on a treadmill. In the presence of low Ang I levels and downregulation of ACE expression/activity, cardiac Ang II levels were significantly higher in aged than young rats, suggesting an ACE-independent response. Aged hearts also displayed significantly increased chymase expression and activity, as well as upregulation of tryptase, a biological marker of mast cells, confirming a mast cell-sourced increase in chymase. Coincidently, cardiac superoxide produced from NADPH oxidase (Nox) was significantly enhanced in aged rats and was normalized by exercise. Conversely, a significant reduction in cardiac expression of ACE2 followed by lower Ang 1-7 levels and downregulation of the Mas receptor (binding protein of Ang 1-7) in aged rats were completely reversed by exercise. In conclusion, local formation of Ang II is increased in aged hearts, and chymase is primarily responsible for this increase. Chronic exercise is able to normalize the age-dependent alterations via compromising chymase/Ang II/angiotensin type 1 receptor/Nox actions while promoting ACE2/Ang 1-7/MasR signaling. NEW & NOTEWORTHY Aging increases angiotensin-converting enzyme (ACE)-independent production of cardiac angiotensin II (Ang II), a response that is driven by chymase in an exercise-reversible manner. These findings highlight chymase, in addition to ACE, as an important therapeutic target in the treatment and prevention of Ang II-induced deterioration of cardiac function in the elderly. Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/renin-angiotensin-system-signaling-in-aged-and-age-exercised-rats/ .

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Dysregulation of the placental renin–angiotensin system in human fetal growth restriction

Reproduction ◽

10.1530/rep-18-0633 ◽

2019 ◽

Vol 158 (3) ◽

pp. 237-245 ◽

Cited By ~ 7

Author(s):

Sarah J Delforce ◽

Eugenie R Lumbers ◽

Stacey J Ellery ◽

Padma Murthi ◽

Kirsty G Pringle

Keyword(s):

Blood Flow ◽

Angiotensin Converting Enzyme ◽

Mrna Expression ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Renin Angiotensin System ◽

Mrna Levels ◽

Ang Ii ◽

Converting Enzyme ◽

Angiotensin System

Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin–angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preeclampsia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were reduced in FGR placentae compared with control (P = 0.012 and 0.018 respectively). Neprilysin (NEP) mRNA expression was lower in FGR placentae compared with control (P = 0.004). mRNA levels of angiotensinogen (AGT) tended to be higher in FGR placentae compared with control (P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.

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Angiotensin-Converting Enzyme 2: The First Decade

International Journal of Hypertension ◽

10.1155/2012/307315 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 89

Author(s):

Nicola E. Clarke ◽

Anthony J. Turner

Keyword(s):

Blood Pressure ◽

Angiotensin Converting Enzyme ◽

Renin Angiotensin System ◽

Ang Ii ◽

Converting Enzyme ◽

Viral Receptor ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Antiproliferative Effects ◽

Potential Use

The renin-angiotensin system (RAS) is a critical regulator of hypertension, primarily through the actions of the vasoactive peptide Ang II, which is generated by the action of angiotensin-converting enzyme (ACE) mediating an increase in blood pressure. The discovery of ACE2, which primarily metabolises Ang II into the vasodilatory Ang-(1-7), has added a new dimension to the traditional RAS. As a result there has been huge interest in ACE2 over the past decade as a potential therapeutic for lowering blood pressure, especially elevation resulting from excess Ang II. Studies focusing on ACE2 have helped to reveal other actions of Ang-(1-7), outside vasodilation, such as antifibrotic and antiproliferative effects. Moreover, investigations focusing on ACE2 have revealed a variety of roles not just catalytic but also as a viral receptor and amino acid transporter. This paper focuses on what is known about ACE2 and its biological roles, paying particular attention to the regulation of ACE2 expression. In light of the entrance of human recombinant ACE2 into clinical trials, we discuss the potential use of ACE2 as a therapeutic and highlight some pertinent questions that still remain unanswered about ACE2.

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COVID-19 susceptibility: potential of ACE2 polymorphisms

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-020-00099-9 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Mayank Chaudhary

Keyword(s):

Blood Pressure ◽

Angiotensin Converting Enzyme ◽

Viral Entry ◽

Serine Proteases ◽

Renin Angiotensin System ◽

Negative Regulator ◽

Main Body ◽

Ang Ii ◽

Converting Enzyme ◽

S Protein

Abstract Background Angiotensin-converting enzyme 2 (ACE2) is a metallopeptidase that primarily functions as a negative regulator of renin angiotensin system (RAS) by converting angiotensin II (Ang II) to angiotensin 1-7. Contrary to this, another RAS component, angiotensin-converting enzyme (ACE) catalyzes synthesis of Ang II from angiotensin I (Ang I) that functions as active compound in blood pressure regulation. This indicates importance of ACE/ACE2 level in regulating blood pressure by targeting Ang II. An outbreak of severe acute respiratory syndrome (SARS) highlighted the additional role of ACE2 as a receptor for SARS coronavirus (SARS-CoV) infection. Main body of the abstract ACE2 is a functional receptor for SARS-CoV and SARS-CoV-2. Activation of spike (S)-protein by either type II transmembrane serine proteases (TTSPs) or cathepsin-mediated cleavage initiates receptor binding and viral entry. In addition to TTSPs, ACE2 can also be trimmed by ADAM 17 (a disintegrin and metalloproteinase 17) that competes for the same receptor. Cleavage by TTSPs activates ACE2 receptor for binding, whereas ADAM17 releases extracellular fragment called soluble ACE2 (sACE2). Structural studies of both ACE2 and S-protein have found critical sites involved in binding mechanism. In addition to studies on structural motifs, few single-nucleotide polymorphism (SNPs) studies have been done to find an association between genetic variants and SARS susceptibility. Though no association was found in those reports, but seeing the non-reproducibility of SNP studies among different ethnic groups, screening of ACE2 SNPs in individual population can be undertaken. Short conclusion Thus, screening for novel SNPs focussing on recently identified critical regions of ACE2 can be targeted to monitor susceptibility towards coronavirus disease 2019 (COVID-19).

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

International Journal of Hypertension ◽

10.1155/2012/147825 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 8

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.

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

International Journal of Hypertension ◽

10.1155/2012/414128 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 27

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.

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

International Journal of Peptides ◽

10.1155/2012/256294 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 176

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.

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Micropuncture determination of nephron function in mice without tissue angiotensin-converting enzyme

AJP Renal Physiology ◽

10.1152/ajprenal.00297.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. F445-F452 ◽

Cited By ~ 27

Author(s):

Seiji Hashimoto ◽

Jon W. Adams ◽

Kenneth E. Bernstein ◽

Jurgen Schnermann

Keyword(s):

Angiotensin Converting Enzyme ◽

Fluid Transport ◽

Renin Angiotensin System ◽

Pressure Change ◽

Renal Tissue ◽

Tubuloglomerular Feedback ◽

Ang Ii ◽

Converting Enzyme ◽

Genetic Changes ◽

Single Nephron

To determine the role of the local renin-angiotensin system in renal function, micropuncture was performed on two lines of mice in which genetic changes to the angiotensin-converting enzyme (ACE) gene markedly reduced or eliminated the expression of renal tissue ACE. Whereas blood pressure is low in one line (ACE 2/2), it is normal in the other (ACE 1/3) due to ectopic hepatic ACE expression. When normalized for renal size, levels of glomerular filtration rate [GFR; μl·min−1·g kidney wt−1 (KW)] and single-nephron GFR (SNGFR; nl·min−1·g KW−1) were similar between wild-type (WT) and ACE 1/3 mice, while both measures were significantly reduced in ACE 2/2 mice (WT: 500 ± 63 and 41.7 ± 3.5; ACE 1/3: 515.8 ± 71 and 44.3 ± 3.3; ACE 2/2: 131.4 ± 23 and 30.3 ± 3.5). Proximal fractional reabsorption was not significantly different between WT and ACE 1/3 mice (51 ± 3.5 and 49 ± 2.3%), and it was increased significantly in ACE 2/2 mice (74 ± 3.5%). Infusion of ANG II (50 ng·kg−1·min−1) increased mean arterial pressure by ∼7 mmHg in all groups of mice and reduced SNGFR in WT and ACE 1/3 mice (to 30.9 ± 2.8 and 31.9 ± 2.5 nl·min−1·g KW−1) while increasing it in ACE 2/2 mice (to 55.3 ± 5.3 nl·min−1·g KW−1) despite an increase in total renal vascular resistance. The tubuloglomerular feedback (TGF) response was markedly reduced in ACE 1/3 mice (stop-flow pressure change −2.5 ± 0.9 mmHg) compared with WT despite similar blood pressures (−8.3 ± 0.6 mmHg). In ACE 2/2 mice, TGF was absent (−0.7 ± 0.2 mmHg). We conclude that the chronic lack of ACE, and presumably ANG II generation, in the proximal tubule was not associated with sustained proximal fluid transport defects. However, renal tissue ACE is an important contributor to TGF.

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