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Hypertension Research : Official... Dec 2003The renin-angiotensin system hormone angiotensin II (Ang II) plays a central role in the pathophysiology of hypertension, cardiac hypertrophy, congestive heart failure,... (Review)
Review
The renin-angiotensin system hormone angiotensin II (Ang II) plays a central role in the pathophysiology of hypertension, cardiac hypertrophy, congestive heart failure, and coronary heart disease. Two distinct subtypes of Ang II receptor, type 1 (AT1) and type 2 (AT2), have been identified, and both have been shown to belong to the G-protein-coupled receptor superfamily (GPCRs). The recent Human Genome Project has revealed more than 1,000 transmembrane (TM) receptors that belong to this superfamily, and it has been estimated that 50% of all clinically used medicines modulate GPCRs activity. Recently, there have been many new insights regarding Ang II receptors and other GPCRs, such as on homo- and hetero-oligomerization, constitutive activation, movement of TM helices, internalization, desensitization and phosphorylation, trafficking, nuclear localization, intracellular protein-induced receptor activation, and receptor-associated proteins. Although AT1 receptor antagonists which prevent Ang II-induced signaling are already clinically available, we here summarize new findings regarding their structure and function, and the possibility of new therapeutic strategies for targeting Ang II receptors through molecular biological techniques.
Topics: Amino Acid Sequence; Humans; Molecular Sequence Data; Protein Structure, Tertiary; Receptor, Angiotensin, Type 1; Structure-Activity Relationship
PubMed: 14717335
DOI: 10.1291/hypres.26.937 -
Experimental Eye Research Oct 2019The renin-angiotensin system (RAS) plays a vital role in cardiovascular physiology and body homeostasis. In addition to circulating RAS, a local RAS exists in the...
The renin-angiotensin system (RAS) plays a vital role in cardiovascular physiology and body homeostasis. In addition to circulating RAS, a local RAS exists in the retina. Dysfunction of local RAS, resulting in increased levels of Angiotensin II (Ang II) and activation of AT1R-mediated signaling pathways, contributes to tissue pathophysiology and end-organ damage. Activation of AT2R on other hand is known to counteract the effects of AT1R activation and produce anti-inflammatory and anti-oxidative effects. We examined the expression of angiotensin receptors in the retina by using transgenic dual reporter mice and by real-time RT-PCR. We further evaluated the effects of C21, a selective agonist of AT2R, in reducing Ang II, lipopolysaccharide (LPS) and hydrogen peroxide induced oxidative stress and inflammatory responses in cultured human ARPE-19 cells. We showed that both AT1Ra and AT2R positive cells are detected in different cell types of the eye, including the RPE/choroid complex, ciliary body/iris, and neural retina. AT1Ra is more abundantly expressed than AT2R in mouse retina, consistent with previous reports. In the neural retina, AT1Ra are also detected in photoreceptors whereas AT2R are mostly expressed in the inner retinal neurons and RGCs. In cultured human RPE cells, activation of AT2R with C21 significantly blocked Ang II, LPS and hydrogen peroxide -induced NF-κB activation and inflammatory cytokine expression; Ang II and hydrogen peroxide-induced reactive oxygen species (ROS) production and MG132-induced apoptosis, comparable to the effects of Angiotensin-(1-7) (Ang-(1-7)), another protective component of the RAS, although C21 is more potent in reducing some of the effects induced by Ang II, whereas Ang-(1-7) is more effective in reducing some of the LPS and hydrogen peroxide-induced effects. These results suggest that activation of AT2R may represent a new therapeutic approach for retinal diseases.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Survival; Cells, Cultured; Cytokines; Gene Expression Regulation; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; RNA, Messenger; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Retina; Retinal Pigment Epithelium; Sulfonamides; Thiophenes
PubMed: 31449794
DOI: 10.1016/j.exer.2019.107770 -
Journal of Neuroinflammation Aug 2020The renin-angiotensin system (RAS) is altered in Parkinson's disease (PD), a disease due to substantia nigra neurodegeneration and whose dopamine-replacement therapy,...
BACKGROUND/AIMS
The renin-angiotensin system (RAS) is altered in Parkinson's disease (PD), a disease due to substantia nigra neurodegeneration and whose dopamine-replacement therapy, using the precursor levodopa, leads to dyskinesias as the main side effect. Angiotensin AT and AT receptors, mainly known for their role in regulating water homeostasis and blood pressure and able to form heterodimers (ATHets), are present in the central nervous system. We assessed the functionality and expression of ATHets in Parkinson disease (PD).
METHODS
Immunocytochemistry was used to analyze the colocalization between angiotensin receptors; bioluminescence resonance energy transfer was used to detect ATHets. Calcium and cAMP determination, MAPK activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify receptor expression in mouse primary cultures and in rat striatal sections.
RESULTS
We confirmed that AT and AT receptors form ATHets that are expressed in cells of the central nervous system. ATHets are novel functional units with particular signaling properties. Importantly, the coactivation of the two receptors in the heteromer reduces the signaling output of angiotensin. Remarkably, ATHets that are expressed in both striatal neurons and microglia make possible that candesartan, the antagonist of AT, increases the effect of AT receptor agonists. In addition, the level of striatal expression increased in the unilateral 6-OH-dopamine lesioned rat PD model and was markedly higher in parkinsonian-like animals that did not become dyskinetic upon levodopa chronic administration if compared with expression in those that became dyskinetic.
CONCLUSION
The results indicate that boosting the action of neuroprotective AT receptors using an AT receptor antagonist constitutes a promising therapeutic strategy in PD.
Topics: Animals; Calcium; Corpus Striatum; Cyclic AMP; Dyskinesia, Drug-Induced; HEK293 Cells; Humans; Levodopa; Mice; Phosphorylation; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Signal Transduction; Substantia Nigra
PubMed: 32807174
DOI: 10.1186/s12974-020-01908-z -
Journal of the... Sep 2011
Review
Topics: Humans; Models, Biological; Receptor Cross-Talk; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Ventricular Remodeling
PubMed: 21880671
DOI: 10.1177/1470320311417750 -
Neurochemistry International Sep 2022We and others have previously shown that angiotensin II receptor type 2 receptor (AT2R) is upregulated in the contralesional hemisphere after stroke in normoglycemic...
We and others have previously shown that angiotensin II receptor type 2 receptor (AT2R) is upregulated in the contralesional hemisphere after stroke in normoglycemic Wistar rats. In this study, we examined the expression of AT2R in type 2 diabetic Goto-Kakizaki (GK) rats and control Wistars after stroke. We also tested the contribution of the contralesional AT2R in recovery after stroke through a specific knockdown of the AT2R in this hemisphere only. Two experiments were conducted. In the first experiment, GK rats were subjected to middle cerebral artery occlusion (MCAO) and treated with the angiotensin II receptor type 1 receptor (AT1R) blocker candesartan or saline at reperfusion. Stroke outcomes, as well as AT2R expression, were examined and compared to control Wistars at 24 h. In the second experiment, localized AT2R knockdown was achieved through intrastriatal injection of short hairpin RNA (shRNA) lentiviral particles or non-targeting control into the left-brain hemisphere of Wistar rats. After 14 days, rats were subjected to right MCAO and treated with the AT2R agonist, Compound 21 (C21), or saline for 7 days. Behavioral outcomes were assessed for up to 10 days. In the first experiment, stroke reduced the expression of AT2R in GK rats. Candesartan treatment failed to improve the neurobehavioral outcomes, preserve vascular integrity or reduce oxidative/nitrative stress or apoptotic markers at 24 h post stroke in these animals. In the second experiment, contralesional AT2R knockdown reduced the C21-mediated functional recovery after stroke. In conclusion, contralesional AT2R upregulation after stroke is blunted in diabetic rats which show reduced sensitivity to post-stroke candesartan treatment. Contralesional AT2R could be involved in C21-mediated functional recovery after stroke.
Topics: Animals; Diabetes Mellitus, Experimental; Imidazoles; Infarction, Middle Cerebral Artery; Rats; Rats, Wistar; Receptor, Angiotensin, Type 2; Stroke; Sulfonamides; Thiophenes
PubMed: 35688299
DOI: 10.1016/j.neuint.2022.105375 -
Journal of Clinical Hypertension... 2001Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are commonly used to treat hypertension and/or a range of progressive end-organ diseases. The... (Review)
Review
Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are commonly used to treat hypertension and/or a range of progressive end-organ diseases. The success of each of these drug classes in disease-state management is without dispute, and has led to speculation that given together the observed response would improve upon that observed with a member of each drug class individually given. Few studies are available, however, which carefully address the effect(s) of the combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker. Review of available studies would seem not to strongly support combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker as preferred therapy in the broad base of general hypertensive patients with or without end-organ disease. Additional clarifying studies are needed to determine if specific patient subsets exist that might benefit from such combination therapy.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hypertension; Receptors, Angiotensin
PubMed: 11723362
DOI: 10.1111/j.1524-6175.2001.00678.x -
Cells May 2020The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system... (Review)
Review
The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system physiology. The RAS is a complicated network of G-protein coupled receptors (GPCRs) (i.e., AT1R, AT2R, MASR, and MRGD) orchestrating the effects of several hormones (i.e., angiotensin II, angiotensin (1-7), and alamandine) produced by protease-based transmembrane receptors (ACE1 and ACE2). Two signaling axes have been identified in the RAS endocrine system that mediate the proliferative actions of angiotensin II (i.e., the AT1R-based pathway) or the anti-proliferative effects of RAS hormones (i.e., the AT2R-, MAS-, and MRGD-based pathways). Disruption of the balance between these two axes can cause different diseases (e.g., cardiovascular pathologies and the severe acute respiratory syndrome coronavirus 2- (SARS-CoV-2)-based COVID-19 disease). It is now accepted that all the components of the RAS endocrine system are expressed in cancer, including cancer of the breast. Breast cancer (BC) is a multifactorial pathology for which there is a continuous need to identify novel drugs. Here, I reviewed the possible roles of both axes of the RAS endocrine network as potential druggable pathways in BC. Remarkably, the analysis of the current knowledge of the different GPCRs of the RAS molecular system not only confirms that AT1R could be considered a drug target and that its inhibition by losartan and candesartan could be useful in the treatment of BC, but also identifies Mas-related GPCR member D (MRGD) as a druggable protein. Overall, the RAS of GPCRs offers multifaceted opportunities for the development of additional compounds for the treatment of BC.
Topics: Angiotensin I; Angiotensin II; Breast Neoplasms; Female; Humans; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System
PubMed: 32471115
DOI: 10.3390/cells9061336 -
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 -
American Journal of Physiology. Renal... Jan 2013Kidneys play a vital role in long-term regulation of blood pressure. This is achieved by actions of many renal and nonrenal factors acting on the kidney that help... (Review)
Review
Kidneys play a vital role in long-term regulation of blood pressure. This is achieved by actions of many renal and nonrenal factors acting on the kidney that help maintain the body's water and electrolyte balance and thus control blood pressure. Several endogenously formed or circulating hormones/peptides, by acting within the kidney, regulate fluid and water homeostasis and blood pressure. Dopamine and angiotensin II are the two key renal factors that, via acting on their receptors and counterregulating each other's function, maintain water and sodium balance. In this review, we provide recent advances in the signaling cascades of these renal receptors, especially at the level of their cross talk, and discuss their roles in blood pressure regulation in the aging process.
Topics: Aging; Angiotensin II; Animals; Blood Pressure; Dopamine; Humans; Hypertension; Kidney; Rats; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Dopamine D1; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance
PubMed: 23097467
DOI: 10.1152/ajprenal.00441.2012 -
Journal of Immunology (Baltimore, Md. :... Sep 2007Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal... (Review)
Review
Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contributes to pathophysiology associated with preeclampsia. The research reviewed here raises the intriguing possibility that preeclampsia may be a pregnancy-induced autoimmune disease.
Topics: Animals; Autoantibodies; Autoimmune Diseases; Female; Humans; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1
PubMed: 17785770
DOI: 10.4049/jimmunol.179.6.3391