ACE2 as therapeutic agent

2020 ◽  
Vol 134 (19) ◽  
pp. 2581-2595
Author(s):  
Qiuhong Li ◽  
Maria B. Grant ◽  
Elaine M. Richards ◽  
Mohan K. Raizada
Keyword(s):  
Therapeutic Agent ◽  
Renin Angiotensin System ◽  
Peptide Hormone ◽  
Experimental Models ◽  
Electrolyte Balance ◽  
Ang Ii ◽  
Angiotensin Converting Enzyme 2 ◽  
Beneficial Effects ◽  
Overwhelming Evidence ◽  
Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

2014 ◽  
Vol 306 (8) ◽  
pp. F812-F821 ◽  
Author(s):  
Jun Mori ◽  
Vaibhav B. Patel ◽  
Tharmarajan Ramprasath ◽  
Osama Abo Alrob ◽  
Jessica DesAulniers ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Beneficial Effects ◽  
Osmotic Pumps ◽  
Characteristic Features ◽  
Transcription 3

The renin-angiotensin system, especially angiotensin II (ANG II), plays a key role in the development and progression of diabetic nephropathy. ANG 1–7 has counteracting effects on ANG II and is known to exert beneficial effects on diabetic nephropathy. We studied the mechanism of ANG 1–7-induced beneficial effects on diabetic nephropathy in db/db mice. We administered ANG 1–7 (0.5 mg·kg−1·day−1) or saline to 5-mo-old db/db mice for 28 days via implanted micro-osmotic pumps. ANG 1–7 treatment reduced kidney weight and ameliorated mesangial expansion and increased urinary albumin excretion, characteristic features of diabetic nephropathy, in db/db mice. ANG 1–7 decreased renal fibrosis in db/db mice, which correlated with dephosphorylation of the signal transducer and activator of transcription 3 (STAT3) pathway. ANG 1–7 treatment also suppressed the production of reactive oxygen species via attenuation of NADPH oxidase activity and reduced inflammation in perirenal adipose tissue. Furthermore, ANG 1–7 treatment decreased lipid accumulation in db/db kidneys, accompanied by increased expressions of renal adipose triglyceride lipase (ATGL). Alterations in ATGL expression correlated with increased SIRT1 expression and deacetylation of FOXO1. The upregulation of angiotensin-converting enzyme 2 levels in diabetic nephropathy was normalized by ANG 1–7. ANG 1–7 treatment exerts renoprotective effects on diabetic nephropathy, associated with reduction of oxidative stress, inflammation, fibrosis, and lipotoxicity. ANG 1–7 can represent a promising therapy for diabetic nephropathy.

scholarly journals Role of angiotensin II in the development of subcellular remodeling in heart failure

2021 ◽  
pp. 352-371
Author(s):  
Sukhwinder K. Bhullar ◽  
Anureet K. Shah ◽  
Naranjan S. Dhalla
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Heart Function ◽  
Critical Role ◽  
Pressure Overload ◽  
Renin Angiotensin System ◽  
Volume Overload ◽  
Experimental Models ◽  
Ang Ii ◽  
Beneficial Effects

The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca2+, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca2+-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dys-function during the progression of heart failure.

Brain angiotensin system: a new promise in the management of epilepsy?

2021 ◽  
Vol 135 (6) ◽  
pp. 725-730
Author(s):  
Alberto Javier Ramos
Keyword(s):  
Therapeutic Potential ◽  
Renin Angiotensin System ◽  
B Cell Lymphoma ◽  
Ang Ii ◽  
Angiotensin System ◽  
Beneficial Effects ◽  
System A ◽  
Pilocarpine Model ◽  
Animal Models Of Epilepsy ◽  
Future Work

Abstract Epilepsy is a highly prevalent neurological disease and anti-epileptic drugs (AED) are almost the unique clinical treatment option. A disbalanced brain renin–angiotensin system (RAS) has been proposed in epilepsy and several reports have shown that angiotensin II (Ang II) receptor-1 (ATR1) activation is pro-inflammatory and pro-epileptogenic. In agreement, ATR1 blockage with the repurposed drug losartan has shown benefits in animal models of epilepsy. Processing of Ang II by ACE2 enzyme renders Ang-(1-7), a metabolite that activates the mitochondrial assembly (Mas) receptor (MasR) pathway. MasR activation presents beneficial effects, facilitating vasodilatation, increasing anti-inflammatory and antioxidative responses. In a recent paper published in Clinical Science, Gomes and colleagues (Clin. Sci. (Lond.) (2020) 134, 2263–2277) performed intracerebroventricular (icv) infusion of Ang-(1-7) in animals subjected to the pilocarpine model of epilepsy, starting after the first spontaneous motor seizure (SMS). They showed that this approach reduced the frequency of SMS, restored animal anxiety, increased exploration, and augmented the hippocampal expression of protective catalase enzyme and antiapoptotic protein B-cell lymphoma 2 (Bcl-2). Interestingly, but surprisingly, Gomes and colleagues showed that MasR expression and mTor activity were reduced in the hippocampus of the epileptic Ang-(1-7) treated animals. These results show that Ang-(1-7) administration could represent a new avenue for developing strategies for the management of epilepsy in clinical settings. However, future work is necessary to evaluate the levels of RAS metabolites and the activity of key enzymes in these experimental interventions to completely understand the therapeutic potential of the brain RAS manipulation in epilepsy.

scholarly journals Evidence for a role of angiotensin converting enzyme 2 in proteinuria of idiopathic nephrotic syndrome

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Roberta da Silva Filha ◽  
Sérgio Veloso Brant Pinheiro ◽  
Thiago Macedo e Cordeiro ◽  
Victor Feracin ◽  
Érica Leandro Marciano Vieira ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Idiopathic Nephrotic Syndrome ◽  
Renin Angiotensin System ◽  
Cross Sectional Study ◽  
Healthy Controls ◽  
Ang Ii ◽  
Cross Sectional ◽  
Angiotensin Converting Enzyme 2 ◽  
Inflammatory Molecules

AbstractIntroduction: Renin angiotensin system (RAS) plays a role in idiopathic nephrotic syndrome (INS). Most studies investigated only the classical RAS axis. Therefore, the aims of the present study were to evaluate urinary levels of RAS molecules related to classical and to counter-regulatory axes in pediatric patients with INS, to compare the measurements with levels in healthy controls and to search for associations with inflammatory molecules, proteinuria and disease treatment. Subjects and methods: This cross-sectional study included 31 patients with INS and 19 healthy controls, matched for age and sex. Patients and controls were submitted to urine collection for measurement of RAS molecules [Ang II, Ang-(1-7), ACE and ACE2] by enzyme immunoassay and cytokines by Cytometric Bead Array. Findings in INS patients were compared according to proteinuria: absent (<150 mg/dl, n = 15) and present (≥150 mg/dl, n = 16). Results: In comparison to controls, INS patients had increased Ang II, Ang-(1-7) and ACE, levels while ACE2 was reduced. INS patients with proteinuria had lower levels of ACE2 than those without proteinuria. ACE2 levels were negatively correlated with 24-h-proteinuria. Urinary concentrations of MCP-1/CCL2 were significantly higher in INS patients, positively correlated with Ang II and negatively with Ang-(1-7). ACE2 concentrations were negatively correlated with IP-10/CXCL-10 levels, which, in turn, were positively correlated with 24-h-proteinuria. Conclusion: INS patients exhibited changes in RAS molecules and in chemokines. Proteinuria was associated with low levels of ACE2 and high levels of inflammatory molecules.

scholarly journals ACE2 Shedding and the Role in COVID-19

2022 ◽  
Vol 11 ◽  
Author(s):  
Jieqiong Wang ◽  
Huiying Zhao ◽  
Youzhong An
Keyword(s):  
Amino Acids ◽  
Viral Entry ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Underlying Mechanism ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Transmembrane Glycoprotein

Angiotensin converting enzyme 2 (ACE2), a transmembrane glycoprotein, is an important part of the renin-angiotensin system (RAS). In the COVID-19 epidemic, it was found to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). ACE2 maintains homeostasis by inhibiting the Ang II-AT1R axis and activating the Ang I (1-7)-MasR axis, protecting against lung, heart and kidney injury. In addition, ACE2 helps transport amino acids across the membrane. ACE2 sheds from the membrane, producing soluble ACE2 (sACE2). Previous studies have pointed out that sACE2 plays a role in the pathology of the disease, but the underlying mechanism is not yet clear. Recent studies have confirmed that sACE2 can also act as the receptor of SARS-COV-2, mediating viral entry into the cell and then spreading to the infective area. Elevated concentrations of sACE2 are more related to disease. Recombinant human ACE2, an exogenous soluble ACE2, can be used to supplement endogenous ACE2. It may represent a potent COVID-19 treatment in the future. However, the specific administration concentration needs to be further investigated.

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 Functional expression of the renin-angiotensin system in human podocytes

2006 ◽  
Vol 290 (3) ◽  
pp. F710-F719 ◽  
Author(s):  
Max C. Liebau ◽  
D. Lang ◽  
J. Böhm ◽  
N. Endlich ◽  
Martin J. Bek ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Functional Expression ◽  
Kidney Cortex ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Angiotensin Receptor ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Beneficial Effects ◽  
Glomerular Proteinuria

Experimental and clinical studies impressively demonstrate that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) significantly reduce proteinuria and retard progression of glomerular disease. The underlying intraglomerular mechanisms are not yet fully elucidated. As podocyte injury constitutes a critical step in the pathogenesis of glomerular proteinuria, beneficial effects of ACEI and ARB may partially result from interference with a local renin-angiotensin system (RAS) in podocytes. The knowledge of expression and function of a local RAS in podocytes is limited. In this study, we demonstrate functional expression of key components of the RAS in differentiated human podocytes: podocytes express mRNA for angiotensinogen, renin, ACE type 1, and the AT1 and AT2 angiotensin receptor subtypes. In Western blot experiments and immunostainings, expression of the AT1 and AT2 receptor was demonstrated both in differentiated human podocytes and in human kidney cortex. ANG II induced a concentration-dependent increase in cytosolic Ca2+ concentration via AT1 receptors in differentiated human podocytes, whereas it did not increase cAMP. Furthermore, ANG II secretion was detected, which was blocked by neither the ACEI captopril nor the renin inhibitor remikiren nor the chymase inhibitor chymostatin. ANG II secretion of podocytes was not increased by mechanical stress. Finally, ANG II was found to increase staurosporine-induced apoptosis in podocytes. We speculate that ACEI and ARB exert their beneficial effects, in part, by interfering with a local RAS in podocytes. Further experiments are required to identify the underlying molecular mechanism(s) of podocyte protection.

Dissociation of Direct and Indirect Effects of Angiotensin II on the Heart

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 683-684
Author(s):  
Jorge P van Kats ◽  
David W Silversides ◽  
Timothy L Reudelhuber
Keyword(s):  
Heart Rate ◽  
Angiotensin Ii ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Renin Angiotensin System ◽  
Cardiac Cells ◽  
Heart Weight ◽  
Ang Ii ◽  
Direct Stimulation ◽  
Beneficial Effects

33 Cardiac angiotensin II (Ang II), either derived from the circulation or locally synthesized, is often suggested to be involved in the structural adaptations occurring in the heart in hypertension and following myocardial infarction. However, it is debated whether the proven beneficial effects of renin-angiotensin system blockade in these pathologies are related to an inhibition of the direct cardiac actions of the peptide. The objective of the present study was to investigate which of the effects of cardiac Ang II are due to direct stimulation of cardiac cells by Ang II. To test for cardiac specific functions of Ang II, transgenic mice were developed that express an Ang II-releasing fusion protein (J Biol Chem 1997;272:12994-99) exclusively in cardiomyocytes. Blood pressure, heart rate, cardiac and plasma Ang II content, Ang II receptor binding and organ morphology were monitored in transgenic (TG) and non-transgenic littermate mice (control). Cardiac Ang II levels in TG mice were 20-40 fold higher than in hearts of control mice (15±3 pg/100 mg ww). In 3 independent founder lines of TG mice, plasma Ang II concentration was not altered as compared to control (119±20 vs. 127±20 pg/mL). The heart weight to body weight ratio in TG mice (4.0±0.1 mg/g) was not different from controls (3.8±0.1 mg/g), neither was systolic pressure (137±4 and 138±7 mm Hg respectively) or heart rate (618±13 and 662±15 bpm respectively). Microscopic inspection of TG hearts did not reveal any differences with control regarding size and number of cardiomyocytes and organization of extracellular matrix proteins. TG mice had not become less sensitive for Ang II signaling since Ang II receptor number was not altered in TG mice (Bmax = 23±3 fmol/mg protein) as compared to control (22±2 fmol/mg protein). Our data show that very high Ang II levels in hearts of TG mice do not lead to myocardial enlargement or affect cardiovascular physiology. We conclude that elevated Ang II in the heart has no direct effects on cardiac cells and we hypothesize that effects of cardiac Ang II become apparent upon altered hemodynamic loading.

scholarly journals Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System

Hypertension ◽  
2020 ◽  
Vol 76 (5) ◽  
pp. 1350-1367 ◽  
Author(s):  
Matthew A. Sparks ◽  
Andrew M. South ◽  
Andrew D. Badley ◽  
Carissa M. Baker-Smith ◽  
Daniel Batlle ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Renin Angiotensin System ◽  
Organ Damage ◽  
Experimental Models ◽  
Multiple Organ ◽  
Host Cells ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Organ Systems

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19—severe acute respiratory syndrome coronavirus 2—gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1–7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1–7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

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.

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