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20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice: NORMALIZATION OF BLOOD PRESSURE BY SODIUM RESTRICTION, HYDROCHLOROTHIAZIDE, OR BLOCKADE OF THE TYPE 1 ANGIOTENSIN II RECEPTOR.
Savas Ü, Wei S, Hsu MH, Falck JR, Guengerich FP, Capdevila JH, Johnson EF
(2016) J Biol Chem 291: 16904-19
MeSH Terms: Angiotensins, Animals, Blood Pressure, Cytochrome P-450 CYP4A, Female, Humans, Hydroxyeicosatetraenoic Acids, Hypertension, Losartan, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Receptor, Angiotensin, Type 1, Renin-Angiotensin System, Sodium Chloride, Dietary, Solute Carrier Family 12, Member 3
Show Abstract · Added March 14, 2018
Male and female homozygous 129/Sv mice carrying four copies of the human cytochrome P450 4A11 gene (CYP4A11) under control of its native promoter (B-129/Sv-4A11(+/+)) develop hypertension (142 ± 8 versus 113 ± 7 mm Hg systolic blood pressure (BP)), and exhibit increased 20-hydroxyeicosatetraenoic acid (20-HETE) in kidney and urine. The hypertension is reversible by a low-sodium diet and by the CYP4A inhibitor HET0016. B-129/Sv-4A11(+/+) mice display an 18% increase of plasma potassium (p < 0.02), but plasma aldosterone, angiotensin II (ANGII), and renin activities are unchanged. This phenotype resembles human genetic disorders with elevated activity of the sodium chloride co-transporter (NCC) and, accordingly, NCC abundance is increased by 50% in transgenic mice, and NCC levels are normalized by HET0016. ANGII is known to increase NCC abundance, and renal mRNA levels of its precursor angiotensinogen are increased 2-fold in B-129/Sv-4A11(+/+), and blockade of the ANGII receptor type 1 with losartan normalizes BP. A pro-hypertensive role for 20-HETE was implicated by normalization of BP and reversal of renal angiotensin mRNA increases by administration of the 20-HETE antagonists 2-((6Z,15Z)-20-hydroxyicosa-6,15-dienamido)acetate or (S)-2-((6Z,15Z)-20-hydroxyicosa-6,15-dienamido)succinate. SGK1 expression is also increased in B-129/Sv-4A11(+/+) mice and paralleled increases seen for NCC. Losartan, HET0016, and 20-HETE antagonists each normalized SGK1 mRNA expression. These results point to a potential 20-HETE dependence of intrarenal angiotensinogen production and ANGII receptor type 1 activation that are associated with increases in NCC and SGK1 and identify elevated P450 4A11 activity and 20-HETE as potential risk factors for salt-sensitive human hypertension by perturbation of the renal renin-angiotensin axis.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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17 MeSH Terms
Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1.
Kraemer MP, Choi H, Reese J, Lamb FS, Breyer RM
(2016) Vascul Pharmacol 84: 47-54
MeSH Terms: Angiotensin II, Animals, Calcium, Dinoprostone, Dose-Response Relationship, Drug, Femoral Artery, Focal Adhesion Kinase 2, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Angiotensin, Type 1, Receptors, Prostaglandin E, EP3 Subtype, Vasoconstriction, rho-Associated Kinases
Show Abstract · Added April 6, 2017
Prostaglandin E2 (PGE2), a cyclooxygenase metabolite that generally acts as a systemic vasodepressor, has been shown to have vasopressor effects under certain physiologic conditions. Previous studies have demonstrated that PGE2 receptor signaling modulates angiotensin II (Ang II)-induced hypertension, but the interaction of these two systems in the regulation of vascular reactivity is incompletely characterized. We hypothesized that Ang II, a principal effector of the renin-angiotensin-aldosterone system, potentiates PGE2-mediated vasoconstriction. Here we demonstrate that pre-treatment of arterial rings with 1nM Ang II potentiated PGE2-evoked constriction in a concentration dependent manner (AUC-Ang II 2.778±2.091, AUC+Ang II 22.830±8.560, ***P<0.001). Using genetic deletion models and pharmacological antagonists, we demonstrate that this potentiation effect is mediated via concurrent signaling between the angiotensin II receptor 1 (AT1) and the PGE2 E-prostanoid receptor 3 (EP3) in the mouse femoral artery. EP3 receptor-mediated vasoconstriction is shown to be dependent on extracellular calcium in combination with proline-rich tyrosine kinase 2 (Pyk2) and Rho-kinase. Thus, our findings reveal a novel mechanism through which Ang II and PGE2 regulate peripheral vascular reactivity.
Copyright © 2016 Elsevier Inc. All rights reserved.
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15 MeSH Terms
Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age.
Zannas AS, McQuoid DR, Payne ME, MacFall JR, Ashley-Koch A, Steffens DC, Potter GG, Taylor WD
(2014) Am J Psychiatry 171: 1214-21
MeSH Terms: Aged, Aged, 80 and over, Aging, Apolipoprotein E4, Cognition Disorders, Endophenotypes, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Hippocampus, Humans, Linkage Disequilibrium, Male, Memory, Episodic, Middle Aged, Organ Size, Polymorphism, Single Nucleotide, Receptor, Angiotensin, Type 1, Renin-Angiotensin System
Show Abstract · Added February 4, 2016
OBJECTIVE - Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. A smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies to date have investigated longitudinally the effects of genetic variation of RAS on the hippocampus.
METHOD - The authors examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. In all, 138 older adults (age ≥60 years) were followed for an average of about 4 years. The participants underwent repeated structural MRI and comprehensive neurocognitive testing, and they were genotyped for four AGTR1 single-nucleotide polymorphisms (SNPs) with low pairwise linkage disequilibrium values and apolipoprotein E (APOE) genotype.
RESULTS - Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, and rs2675511) were independently associated with accelerated hippocampal volume loss over the 4-year follow-up period in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss.
CONCLUSIONS - Risk genetic variants of the RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders.
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20 MeSH Terms
The central renin-angiotensin system and sympathetic nerve activity in chronic heart failure.
Zucker IH, Xiao L, Haack KK
(2014) Clin Sci (Lond) 126: 695-706
MeSH Terms: Animals, Chronic Disease, Exercise, Heart Failure, Humans, Peptidyl-Dipeptidase A, Receptor, Angiotensin, Type 1, Renin-Angiotensin System, Sympathetic Nervous System
Show Abstract · Added August 5, 2014
CHF (chronic heart failure) is a multifactorial disease process that is characterized by overactivation of the RAAS (renin-angiotensin-aldosterone system) and the sympathetic nervous system. Both of these systems are chronically activated in CHF. The RAAS consists of an excitatory arm involving AngII (angiotensin II), ACE (angiotensin-converting enzyme) and the AT1R (AngII type 1 receptor). The RAAS also consists of a protective arm consisting of Ang-(1-7) [angiotensin-(1-7)], the AT2R (AngII type 2 receptor), ACE2 and the Mas receptor. Sympatho-excitation in CHF is driven, in large part, by an imbalance of these two arms, with an increase in the AngII/AT1R/ACE arm and a decrease in the AT2R/ACE2 arm. This imbalance is manifested in cardiovascular-control regions of the brain such as the rostral ventrolateral medulla and paraventricular nucleus in the hypothalamus. The present review focuses on the current literature that describes the components of these two arms of the RAAS and their imbalance in the CHF state. Moreover, the present review provides additional evidence for the relevance of ACE2 and Ang-(1-7) as key players in the regulation of central sympathetic outflow in CHF. Finally, we also examine the effects of exercise training as a therapeutic strategy and the molecular mechanisms at play in CHF, in part, because of the ability of exercise training to restore the balance of the RAAS axis and sympathetic outflow.
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9 MeSH Terms
AGTR1 gene variation: association with depression and frontotemporal morphology.
Taylor WD, Benjamin S, McQuoid DR, Payne ME, Krishnan RR, MacFall JR, Ashley-Koch A
(2012) Psychiatry Res 202: 104-9
MeSH Terms: Aged, Aged, 80 and over, Depressive Disorder, Major, Female, Frontal Lobe, Gene Frequency, Genetic Association Studies, Genotype, Humans, Image Processing, Computer-Assisted, Logistic Models, Magnetic Resonance Imaging, Male, Mental Status Schedule, Middle Aged, Polymorphism, Single Nucleotide, Receptor, Angiotensin, Type 1, Temporal Lobe
Show Abstract · Added May 20, 2014
The renin-angiotensin system (RAS) is implicated in the response to physiological and psychosocial stressors, but its role in stress-related psychiatric disorders is poorly understood. We examined if variation in AGTR1, the gene coding for the type 1 angiotensin II receptor (AT(1)R), is associated with a diagnosis of depression and differences in white matter hyperintensities and frontotemporal brain volumes. Participants comprised 257 depressed and 116 nondepressed elderly Caucasian subjects who completed clinical assessments and provided blood samples for genotyping. We used a haplotype-tagging single nucleotide polymorphism (htSNP) analysis to test for variation in AGTR1. For measurement of hyperintense lesions, 1.5 Tesla magnetic resonance imaging (MRI) data were available on 33 subjects. For measurements of the hippocampus and dorsolateral prefrontal cortex (dlPFC), 3 Tesla MRI data were available on 70 subjects. Two htSNPs exhibited statistically significant frequency differences between diagnostic cohorts: rs10935724 and rs12721331. Although hyperintense lesion volume did not significantly differ by any htSNP, dlPFC and hippocampus volume differed significantly for several htSNPs. Intriguingly, for those htSNPs differing significantly for both dlPFC and hippocampus volume, the variant associated with smaller dlPFC volume was associated with larger hippocampal volume. This supports the idea that genetic variation in AGTR1 is associated with depression and differences in frontotemporal morphology.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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18 MeSH Terms
Studies of the T-cell angiotensin receptor using cre-lox technology: an unan-T-cellpated result.
Harrison DG, Guzik TJ
(2012) Circ Res 110: 1543-5
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Hypertension, Kidney, Receptor, Angiotensin, Type 1
Added December 10, 2013
1 Communities
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5 MeSH Terms
Ontogeny of angiotensin type 2 and type 1 receptor expression in mice.
Gao J, Chao J, Parbhu KJ, Yu L, Xiao L, Gao F, Gao L
(2012) J Renin Angiotensin Aldosterone Syst 13: 341-52
MeSH Terms: Animals, Animals, Newborn, Antibodies, Brain, Cell Membrane, Cytosol, Fetus, Gene Expression Regulation, Developmental, Male, Mice, Mice, Inbred C57BL, Models, Biological, RNA, Messenger, Rats, Real-Time Polymerase Chain Reaction, Receptor, Angiotensin, Type 1, Receptor, Angiotensin, Type 2, Spinal Cord
Show Abstract · Added August 5, 2014
In the current experiment, we determined angiotensin type 2 receptor (AT2R) and angiotensin type 1 receptor (AT1R) protein expression by western blot analysis in developing normal mice. The results indicate that: (1) in all detected brain regions and in the spinal cord, adult mice exhibited significantly higher AT2R expression and lower AT1R expression in total protein extracts compared to fetuses and neonates; (2) other major organs, including heart, lung, liver and kidney, exhibited the same expression pattern as the brain and spinal cord; (3) reciprocal changes in AT2R and AT1R expression were found in the total protein extracts from the brainstems of mice from one-day prenatal to six weeks of age, and there was a negative correlation between AT2R and AT1R protein expression; (4) in both membrane and cytosolic fractions from the brainstem, adult mice exhibited higher AT2R and lower AT1R expression than did fetuses and neonates; and (5) in the brainstem, there were no significant differences in AT2R and AT1R messenger RNA (mRNA) levels among fetal, neonatal and adult mice. The above results reconfirmed our previous finding in rats that adult animals have higher AT2R and lower AT1R expression compared to fetuses and neonates. These data imply an involvement of AT1R in fetal development and of AT2R in adult function.
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18 MeSH Terms
Top advances in functional genomics and translational biology for 2011.
Barth AS, Ferguson JF, Musunuru K
(2012) Circ Cardiovasc Genet 5: 143-5
MeSH Terms: ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Animals, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Drosophila, Genome-Wide Association Study, Genomics, Humans, Kinesin, Mice, Proteomics, Receptor, Angiotensin, Type 1, Receptor, Angiotensin, Type 2, Translational Medical Research
Added January 20, 2015
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15 MeSH Terms
Angiotensin II induces epithelial-to-mesenchymal transition in renal epithelial cells through reactive oxygen species/Src/caveolin-mediated activation of an epidermal growth factor receptor-extracellular signal-regulated kinase signaling pathway.
Chen J, Chen JK, Harris RC
(2012) Mol Cell Biol 32: 981-91
MeSH Terms: Angiotensin II, Animals, Caveolins, Cell Differentiation, Cell Line, Epithelial Cells, Epithelial-Mesenchymal Transition, ErbB Receptors, Extracellular Signal-Regulated MAP Kinases, Kidney Tubules, Proximal, Phosphorylation, Reactive Oxygen Species, Receptor, Angiotensin, Type 1, Signal Transduction, Swine, src-Family Kinases
Show Abstract · Added August 19, 2013
Chronic activation of the renin-angiotensin system plays a deleterious role in progressive kidney damage, and the renal proximal tubule is known to play an important role in tubulointerstitial fibrosis; however, the underlying molecular mechanism is unclear. Here we report that in the proximal tubule-like LLCPKcl4 cells expressing angiotensin II (Ang II) type 1 receptor, Ang II induced changes in cell morphology and expression of epithelial-to-mesenchymal transition (EMT) markers, which were inhibited by the miotogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK)-activating kinase (MEK) inhibitor PD98059 or the Src kinase inhibitor PP2. Ang II-stimulated phosphorylation of caveolin-1 (Cav) at Y14 and epidermal growth factor receptor (EGFR) at Y845 and induced association of these phosphoproteins in caveolin-enriched lipid rafts, thereby leading to prolonged EGFR-ERK signaling that was inhibited by Nox4 small interfering RNA (siRNA) and Src siRNA. Two different antioxidants not only inhibited phosphorylation of Src at Y416 but also blocked the EGFR-ERK signaling. Moreover, erlotinib (the EGFR tyrosine kinase inhibitor), EGFR siRNA, and Cav siRNA all inhibited both prolonged EGFR-ERK signaling and phenotypic changes induced by Ang II. Thus, this report provides the first evidence that reactive oxygen species (ROS)/Src-dependent activation of persistent Cav-EGFR-ERK signaling mediates renal tubular cell dedifferentiation and identifies a novel molecular mechanism that may be involved in progressive renal injury caused by chronic exposure to Ang II.
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16 MeSH Terms
Fiber tract-specific white matter lesion severity Findings in late-life depression and by AGTR1 A1166C genotype.
Taylor WD, Zhao Z, Ashley-Koch A, Payne ME, Steffens DC, Krishnan RR, Hauser E, MacFall JR
(2013) Hum Brain Mapp 34: 295-303
MeSH Terms: Aged, Antidepressive Agents, Brain Mapping, Brain-Derived Neurotrophic Factor, Cohort Studies, Depressive Disorder, Major, Diagnostic and Statistical Manual of Mental Disorders, Diffusion Tensor Imaging, Female, Genotype, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Fibers, Myelinated, Neural Pathways, Polymerase Chain Reaction, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Receptor, Angiotensin, Type 1
Show Abstract · Added May 20, 2014
Past work demonstrated that late-life depression is associated with greater severity of ischemic cerebral hyperintense white matter lesions, particularly frontal lesions. However, these lesions are also associated with other neuropsychiatric deficits, so these clinical relationships may depend on which fiber tracts are damaged. We examined the ratio of lesion to nonlesioned white matter tissue within multiple fiber tracts between depressed and nondepressed elders. We also sought to determine if the AGTR1 A1166C and BDNF Val66Met polymorphisms contributed to vulnerability to lesion development in discrete tracts. The 3T structural MR images and blood samples for genetic analyses were acquired on 54 depressed and 37 nondepressed elders. Lesion maps were created through an automated tissue segmentation process and applied to a probabilistic white matter fiber tract atlas allowing for identification of the fraction of the tract occupied by lesion. The depressed cohort exhibited a significantly greater lesion ratio only in the left upper cingulum near the cingulate gyrus (F((1,86)) = 4.62, P = 0.0344), supporting past work implicating cingulate dysfunction in the pathogenesis of depression. In the 62 Caucasian subjects with genetic data, AGTR1 C1166 carriers exhibited greater lesion ratios across multiple tracts including the anterior thalamic radiation and inferior fronto-occipital fasciculus. In contrast, BDNF Met allele carriers exhibited greater lesion ratios only in the frontal corpus callosum. Although these findings did not survive correction for multiple comparisons, this study supports our hypothesis and provides preliminary evidence that genetic differences related to vascular disease may increase lesion vulnerability differentially across fiber tracts.
Copyright © 2011 Wiley Periodicals, Inc.
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21 MeSH Terms