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Proceedings of the National Academy of... Aug 2020There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research...
There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research applications. However, there are few antibody ligands targeting GPCRs outside of the chemokine receptor group. GPCRs are challenging targets for conventional antibody discovery methods, as many are highly conserved across species, are biochemically unstable upon purification, and possess deeply buried ligand-binding sites. Here, we describe a selection methodology to enrich for functionally modulatory antibodies using a yeast-displayed library of synthetic camelid antibody fragments called "nanobodies." Using this platform, we discovered multiple nanobodies that act as antagonists of the angiotensin II type 1 receptor (AT1R). Following angiotensin II infusion in mice, we found that an affinity matured nanobody antagonist has comparable antihypertensive activity to the angiotensin receptor blocker (ARB) losartan. The unique pharmacology and restricted biodistribution of nanobody antagonists may provide a path for treating hypertensive disorders when small-molecule drugs targeting the AT1R are contraindicated, for example, in pregnancy.
Topics: Angiotensin Receptor Antagonists; Animals; Antibody Affinity; Blood Pressure; Cell Line; Humans; Mice; Receptors, Angiotensin; Single-Domain Antibodies
PubMed: 32753386
DOI: 10.1073/pnas.2009029117 -
The FEBS Journal Mar 2020Obesity is often associated with high systemic and local renin-angiotensin system (RAS) activity in adipose tissue. Adipose-derived mesenchymal stem/stromal cells... (Review)
Review
Obesity is often associated with high systemic and local renin-angiotensin system (RAS) activity in adipose tissue. Adipose-derived mesenchymal stem/stromal cells (ADSCs), responsible for adipose tissue growth upon high-fat diet, express multiple angiotensin II receptor isoforms, including angiotensin II type 1 receptor (AT R), angiotensin II type 2 receptor (AT R), Mas and Mas-related G protein-coupled receptor D. Although AT R is expressed on most ADSCs, other angiotensin receptors are co-expressed on a small subpopulation of the cells, a phenomenon that results in a complex response pattern. Following AT R activation, the effects are transient due to rapid receptor internalisation. This short-lived effect can be prevented by heteromerisation with AT R, a particularly important strategy for the regulation of ADSC differentiation and secretory activity. Heteromeric AT R might be especially important for the generation of thermogenic beige adipocytes. This review summarises current data regarding the regulation of adipose tissue renewal and particularly ADSC adipogenic differentiation and secretory activity by RAS, with an emphasis on AT R and its effects. We reveal a new scheme that implicates AT R into the regulation of ADSC hormonal sensitivity.
Topics: Adipose Tissue; Animals; Cell Proliferation; Humans; Receptor, Angiotensin, Type 2
PubMed: 31899581
DOI: 10.1111/febs.15200 -
American Journal of Physiology. Heart... Apr 2018It has become clear that the vasoactive peptide angiotensin II, like other so-called intracrines, can act in the intracellular space. Evidence has accumulated indicating... (Review)
Review
It has become clear that the vasoactive peptide angiotensin II, like other so-called intracrines, can act in the intracellular space. Evidence has accumulated indicating that such angiotensin II activity can be upregulated in disease states and cause pathology. Indeed, other intracrines appear to be involved in disease pathogenesis as well. At the same time, nitric oxide, potentially a cell protective factor, has been shown to be upregulated by intracellular angiotensin II. Recently data have been developed indicating that other potentially protective factors are directly upregulated at neuronal nuclei by angiotensin II. This led to the suggestion that intracellular angiotensin II is cell protective and not pathological. Here, the data on both sides of this issue and a possible resolution are discussed. In summary, there is evidence for both protective and pathological actions of intracellular angiotensin, just as there is abundant evidence derived from whole animal physiology to indicate that angiotensin-driven signaling cascades, including angiotensin II type 2 receptor- and Mas receptor-mediated events, can mitigate the effects of the angiotensin II/angiotensin II type 1 receptor axis (25). This mitigation does not negate the physiological and pathological importance of angiotensin II/angiotensin II type 1 receptor action but does expand our understanding of the workings of both intracellular and extracellular angiotensin II.
Topics: Angiotensin II; Animals; Cell Nucleus; Humans; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction
PubMed: 29351452
DOI: 10.1152/ajpheart.00632.2017 -
American Journal of Physiology. Heart... Jun 2019A growing body of data provides strong evidence that intracellular angiotensin II (ANG II) plays an important role in mammalian cell function and is involved in the... (Review)
Review
A growing body of data provides strong evidence that intracellular angiotensin II (ANG II) plays an important role in mammalian cell function and is involved in the pathogenesis of human diseases such as hypertension, diabetes, inflammation, fibrosis, arrhythmias, and kidney disease, among others. Recent studies also suggest that intracellular ANG II exerts protective effects in cells during high extracellular levels of the hormone or during chronic stimulation of the local tissue renin-angiotensin system (RAS). Notably, the intracellular RAS (iRAS) described in neurons, fibroblasts, renal cells, and cardiomyocytes provided new insights into regulatory mechanisms mediated by intracellular ANG II type 1 (ATRs) and 2 (ATRs) receptors, particularly, in mitochondria and nucleus. For instance, ANG II through nuclear ATRs promotes protective mechanisms by stimulating the ATR signaling cascade, which involves mitochondrial ATRs and Mas receptors. The stimulation of nuclear ANG II receptors enhances mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ coactivator-1α and increases sirtuins activity, thus protecting the cell against oxidative stress. Recent studies in ANG II-induced preconditioning suggest that plasma membrane ATR stimulation exerts protective effects against cardiac ischemia-reperfusion by modulating mitochondrial ATR and ATR signaling. These studies indicate that iRAS promotes the protection of cells through nuclear ATR signaling, which, in turn, promotes ATR-dependent processes in mitochondria. Thus, despite abundant data on the deleterious effects of intracellular ANG II, a growing body of studies also supports a protective role for iRAS that could be of relevance to developing new therapeutic strategies. This review summarizes and discusses previous studies on the role of iRAS, particularly emphasizing the protective and counterbalancing actions of iRAS, mitochondrial ANG II receptors, and their implications for organ protection.
Topics: Angiotensin II; Animals; Humans; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction
PubMed: 30978131
DOI: 10.1152/ajpheart.00772.2018 -
Vascular Health and Risk Management 2015Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments... (Review)
Review
Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction.
Topics: Aminobutyrates; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Clinical Trials as Topic; Drug Combinations; Heart Failure; Humans; Hypertension; Indans; Natriuretic Peptide, Brain; Neprilysin; Propionates; Pyridines; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors; Stroke Volume; Tetrazoles; Thiazepines; Valsartan
PubMed: 26082640
DOI: 10.2147/VHRM.S55630 -
Dermatologic Therapy Nov 2020COVID-19 is an outbreak of viral pneumonia which became a global health crisis, and the risk of morbidity and mortality of people with obesity are higher. SARS-CoV-2,... (Review)
Review
COVID-19 is an outbreak of viral pneumonia which became a global health crisis, and the risk of morbidity and mortality of people with obesity are higher. SARS-CoV-2, the pathogen of COVID-19, enters into cells through binding to the Angiotensin Converting Enzyme (ACE) homolog-2 (ACE2). ACE2 is a regulator of two contrary pathways in renin angiotensin system (RAS): ACE-Ang-II-AT1R axis and ACE2-Ang 1-7-Mas axis. Viral entry process eventuates in downregulation of ACE2 and subsequent activation of ACE-Ang-II-AT1R axis. ACE-Ang II-AT1R axis increases lipid storage, reduces white-to-beige fat conversion and plays role in obesity. Conversely, adipose tissue is an important source of angiotensin, and obesity results in increased systemic RAS. ACE-Ang-II-AT1R axis, which has proinflammatory, profibrotic, prothrombotic, and vasoconstrictive effects, is potential mechanism of more severe SARS-CoV-2 infection. The link between obesity and severe COVID-19 may be attributed to ACE2 consumption and subsequent ACE-Ang-II-AT1R axis activation. Therefore, patients with SARS-CoV-2 infection may benefit from therapeutic strategies that activate ACE2-Ang 1-7-Mas axis, such as Ang II receptor blockers (ARBs), ACE inhibitors (ACEIs), Mas receptor agonists and ACE2.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; COVID-19; Humans; Obesity; Pneumonia, Viral; Receptors, Angiotensin; Renin-Angiotensin System; SARS-CoV-2; Severity of Illness Index; COVID-19 Drug Treatment
PubMed: 32645228
DOI: 10.1111/dth.13989 -
Molecular Medicine Reports Nov 2022COVID‑19 patients with severe infection have been observed to have elevated auto‑antibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1... (Review)
Review
COVID‑19 patients with severe infection have been observed to have elevated auto‑antibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1 receptor type A (ETAR), compared with healthy controls and patients with favorable (mild) infection. AT1R and ETAR are G protein‑coupled receptors, located on vascular smooth muscle cells, fibroblasts, immune and endothelial cells, and are activated by angiotensin II (Ang II) and ET1 respectively. AAs that are specific for these receptors have a functional role similar to the natural ligands, but with a more prolonged vasoconstrictive effect. They also induce the production of fibroblast collagen, the release of reactive oxygen species and the secretion of proinflammatory cytokines (including IL‑6, IL‑8 and TNF‑α) by immune cells. Despite the presence of AAs in severe COVID‑19 infected patients, their contribution and implication in the severity of the disease is still not well understood and further studies are warranted. The present review described the major vascular homeostasis systems [ET and renin‑angiotensin‑aldosterone system (RAAS)], the vital regulative role of nitric oxide, the AAs, and finally the administration of angiotensin II receptor blockers (ARBs), so as to provide more insight into the interplay that exists among these components and their contribution to the severity, prognosis and possible treatment of COVID‑19.
Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; COVID-19; Collagen; Endothelial Cells; Endothelins; Humans; Interleukin-6; Interleukin-8; Nitric Oxide; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, Endothelin A; Receptors, Angiotensin; Tumor Necrosis Factor-alpha; Vascular Diseases
PubMed: 36196882
DOI: 10.3892/mmr.2022.12867 -
Trends in Pharmacological Sciences Jul 2021G protein-coupled angiotensin II receptors, ATR and ATR, are integral components of the renin-angiotensin system (RAS) that regulates blood pressure and fluid balance in... (Review)
Review
G protein-coupled angiotensin II receptors, ATR and ATR, are integral components of the renin-angiotensin system (RAS) that regulates blood pressure and fluid balance in humans. While ATR is a well-established target of angiotensin receptor blockers (ARBs) for managing hypertension and a prime system for studying biased signaling, ATR has been recognized as a promising target against neuropathic pain and lung fibrosis. In this review, we discuss how recent structural advances illuminate ligand-binding modes and subtype selectivity, shared and distinct features of the receptors, their transducer-coupling patterns, and downstream signaling responses. We also underscore the key ATR aspects that require further studies to fully appreciate the mechanistic framework that fine-tunes their cellular and physiological functions, providing untapped potential for drug discovery.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Humans; Ligands; Receptor, Angiotensin, Type 1; Renin-Angiotensin System
PubMed: 33985815
DOI: 10.1016/j.tips.2021.04.006 -
Current Hypertension Reports Jul 2020To review recent data that suggest opposing effects of brain angiotensin type-1 (ATR) and type-2 (ATR) receptors on blood pressure (BP). Here, we discuss recent studies... (Review)
Review
PURPOSE OF REVIEW
To review recent data that suggest opposing effects of brain angiotensin type-1 (ATR) and type-2 (ATR) receptors on blood pressure (BP). Here, we discuss recent studies that suggest pro-hypertensive and pro-inflammatory actions of ATR and anti-hypertensive and anti-inflammatory actions of ATR. Further, we propose mechanisms for the interplay between brain angiotensin receptors and neuroinflammation in hypertension.
RECENT FINDINGS
The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular physiology. This includes brain ATR and ATR, both of which are expressed in or adjacent to brain regions that control BP. Activation of ATR within those brain regions mediate increases in BP and cause neuroinflammation, which augments the BP increase in hypertension. The fact that ATR and ATR have opposing actions on BP suggests that ATR and ATR may have similar opposing actions on neuroinflammation. However, the mechanisms by which brain ATR and ATR mediate neuroinflammatory responses remain unclear. The interplay between brain angiotensin receptor subtypes and neuroinflammation exacerbates or protects against hypertension.
Topics: Angiotensin I; Brain; Humans; Hypertension; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin
PubMed: 32661792
DOI: 10.1007/s11906-020-01062-0 -
Current Hypertension Reports May 2018Angiotensin type 2 receptor (ATR) and receptor Mas (MasR) are part of the "protective arm" of the renin angiotensin system. Gene and pharmacological manipulation studies... (Review)
Review
PURPOSE OF REVIEW
Angiotensin type 2 receptor (ATR) and receptor Mas (MasR) are part of the "protective arm" of the renin angiotensin system. Gene and pharmacological manipulation studies reveal that ATR and MasR are involved in natriuretic, vasodilatory, and anti-inflammatory responses and in lowering blood pressure in various animal models under normal and pathological conditions such as salt-sensitive hypertension, obesity, and diabetes. The scope of this review is to discuss co-localization and heterodimerization as potential molecular mechanisms of ATR- and MasR-mediated functions including antihypertensive activities.
RECENT FINDINGS
Accumulating evidences show that ATR and MasR are co-localized, make a heterodimer, and are functionally interdependent in producing their physiological responses. Moreover, ang-(1-7) preferably may be an ATR-biased agonist while acting as a MasR agonist. The physical interactions of ATR and MasR appear to be an important mechanism by which these receptors are involved in blood pressure regulation and antihypertensive activity. Whether heteromers of these receptors influence affinity or efficacy of endogenous or synthetic agonists remains a question to be considered.
Topics: Animals; Blood Pressure; Dimerization; Humans; Hypertension; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System
PubMed: 29717388
DOI: 10.1007/s11906-018-0845-3