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Kidney International Sep 1990The purpose of these studies was to quantitatively assess the role of endogenous angiotensin II activity in controlling transport in the proximal convoluted tubule (PCT)... (Comparative Study)
Comparative Study
The purpose of these studies was to quantitatively assess the role of endogenous angiotensin II activity in controlling transport in the proximal convoluted tubule (PCT) and whole nephron. We used the nonpeptide angiotensin II receptor antagonist DuP 753, which lacks the agonist and kinin/prostaglandin-inducing properties of saralasin and captopril, respectively. During in vivo microperfusion in the Munich-Wistar rat, we found that DuP 753 had a powerful inhibitory effect on bicarbonate (370 +/- 3 to 200 +/- 9 pEq/mm.min, P less than 0.001), chloride (214 +/- 3 to 105 +/- 9 pEq/mm.min, P less than 0.001), and water (5.2 +/- 0.1 to 2.8 +/- 0.2 nl/mm.min, P less than 0.001) absorption in the S1 subsegment of the PCT. At maximally effective doses, DuP 753 (10 mg/kg i.v.) was significantly more effective than was captopril (3 mg/kg i.v.) in inhibiting sodium chloride transport in the S1 PCT. DuP 753 is the most potent diuretic ever described in this segment. Consistent with the axial decline of angiotensin II receptor density in the PCT, DuP 753 was a less effective transport inhibitor in the S2 subsegment of the PCT, similar to captopril. Though downstream reabsorptive elements partially compensate for the action in the earliest segment of the nephron, we also showed using free-flow micropuncture and clearance techniques that DuP 753 induces a substantial diuresis, natriuresis and chloruresis. In conclusion, the marked decrease in S1 PCT fluid and electrolyte absorption induced by DuP 753 indicates that endogenous angiotensin II exerts significant tonic support of proximal transport in vivo.
Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Captopril; Diuretics; Imidazoles; Kidney Tubules, Proximal; Losartan; Male; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Tetrazoles
PubMed: 2232490
DOI: 10.1038/ki.1990.228 -
Cancer Research Mar 2018The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In...
The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NFκB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NFκB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell-intrinsic responses that include proliferation, migration, and invasion. In addition, CBM-dependent activation of NFκB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NFκB signaling in AGTR1 breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II-dependent NFκB signaling pathways to improve the treatment of this breast cancer subset. These findings offer a mechanistic rationale to explore the repurposing of drugs that target angiotensin action to improve the treatment of AGTR1-expressing breast cancers. .
Topics: Animals; Apoptosis; B-Cell CLL-Lymphoma 10 Protein; Biomarkers, Tumor; Breast Neoplasms; CARD Signaling Adaptor Proteins; Cell Movement; Cell Proliferation; Chick Embryo; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; NF-kappa B; Neovascularization, Pathologic; Prognosis; RNA, Small Interfering; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 29259013
DOI: 10.1158/0008-5472.CAN-17-1089 -
Proceedings of the National Academy of... Jan 2000Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the AII type 1 receptor (AT1R). AII...
Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the AII type 1 receptor (AT1R). AII has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of AII at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse alpha-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases.
Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Angiotensin Receptor Antagonists; Animals; Atrial Natriuretic Factor; Binding, Competitive; Blotting, Northern; Cardiomegaly; Gene Expression Regulation; Heart Atria; Heart Ventricles; Humans; Imidazoles; Immunohistochemistry; Losartan; Mice; Mice, Transgenic; Myocardium; Phenotype; Pyridines; RNA, Messenger; Radioligand Assay; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tissue Distribution; Transgenes; Ventricular Remodeling
PubMed: 10639182
DOI: 10.1073/pnas.97.2.931 -
Zhongguo Yao Li Xue Bao = Acta... Jul 1995To study the effects of hypoxia on the vasoconstrictive response and the angiotensin II (Ang II) content and its receptor.
AIM
To study the effects of hypoxia on the vasoconstrictive response and the angiotensin II (Ang II) content and its receptor.
METHODS
Hypoxia was induced in isolated aorta of guinea pig by gassing N2. The vasoconstrictive response of aorta to Ang II was recorded. Ang II content and its receptor were measured by radioimmuoassay.
RESULTS
Ang 3-3000 nmol L-1 increased the contractile response of aorta. Hypoxia amplified the vasoconstrictive effect of Ang II. The concentration of Ang II were 44 +/- 24 and 50 +/- 17 pg/g wet wt (n = 10), respectively in non-hypoxic and hypoxic aortae. The receptor density in non-hypoxic aorta was 17 +/- 3 fmol mg-1, and that in hypoxia was 33 +/- 5 fmol mg-1 (P < 0.01).
CONCLUSION
The enhancement of the vasoconstrictive action of Ang II by hypoxia is due to the increase in the angiotensin receptor density, but not associated with the changes in the Ang II content in hypoxic aorta of guinea pig.
Topics: Angiotensin II; Animals; Aorta; Cell Hypoxia; Female; Guinea Pigs; In Vitro Techniques; Male; Receptors, Angiotensin; Vasoconstriction
PubMed: 7668114
DOI: No ID Found -
The Journal of Clinical Investigation Apr 1994Although both rat cardiac nonmyocytes (mostly fibroblasts) and cardiomyocytes have a functional angiotensin II (AngII) receptor, the regulation mechanism of its subtype...
Although both rat cardiac nonmyocytes (mostly fibroblasts) and cardiomyocytes have a functional angiotensin II (AngII) receptor, the regulation mechanism of its subtype expression in the rat heart remains unknown. In this study, by using a binding assay and a competitive reverse-transcriptase polymerase chain reaction, we examined the regulation of AngII types 1a and 1b (AT1a-R and AT1b-R) and type 2 receptor (AT2-R) expression in embryonal day 19 (E19) and neonatal (1-d) rat cardiac fibroblasts and cardiomyocytes. The number of AT2-R in E19 fibroblasts was dramatically decreased (from 305 to 41 fmol/mg protein) in 1-d fibroblasts, whereas that of AT1-R and the mRNA levels remained unchanged. The ratio of AT1a-R to AT1b-R mRNA in both E19 and 1-d fibroblasts was 9:1. The number of AT2-R in E19 cardiomyocytes was also significantly decreased (from 178 to 87 fmol/mg protein) in 1-d cardiomyocytes, whereas the magnitude was less prominent compared with that in fibroblasts. AT1-R expression remained unaltered in E19 and 1-d cardiomyocytes. In E19 and 1-d cardiomyocytes, the AT1b-R mRNA level was 1.5-fold higher than that of AT1a-R mRNA. Dexamethasone induced significant increases in AT1a-R mRNA (2.1-fold) and numbers (1.8-fold) without changing the affinity, whereas neither AT1b-R mRNA nor the number of AT2-R was affected by dexamethasone. The AT1a-R gene transcription rate, determined by means of a nuclear run-off assay, was increased (2-fold) by dexamethasone. The half-life of AT1a-R mRNA (18 h) was unchanged by dexamethasone. These data indicate that AngII receptor subtype expression in the rat heart is regulated in a cell- and subtype-specific manner.
Topics: Angiotensin II; Animals; Base Sequence; Cells, Cultured; Dexamethasone; Fibroblasts; Gene Expression Regulation; Molecular Sequence Data; Myocardium; Rats; Rats, Wistar; Receptors, Angiotensin
PubMed: 8163661
DOI: 10.1172/JCI117139 -
Proceedings of the National Academy of... May 1999The vast majority of the known biological effects of the renin-angiotensin system are mediated by the type-1 (AT1) receptor, and the functions of the type-2 (AT2)...
The vast majority of the known biological effects of the renin-angiotensin system are mediated by the type-1 (AT1) receptor, and the functions of the type-2 (AT2) receptor are largely unknown. We investigated the role of the AT2 receptor in the vascular and renal responses to physiological increases in angiotensin II (ANG II) in mice with targeted deletion of the AT2 receptor gene. Mice lacking the AT2 receptor (AT2-null mice) had slightly elevated systolic blood pressure (SBP) compared with that of wild-type (WT) control mice (P < 0.0001). In AT2-null mice, infusion of ANG II (4 pmol/kg/min) for 7 days produced a marked and sustained increase in SBP [from 116 +/- 0.5 to 208 +/- 1 mmHg (P < 0.0001) (1 mmHg = 133 Pa)] and reduction in urinary sodium excretion (UNaV) [from 0.6 +/- 0.01 to 0.05 +/- 0.002 mM/day (P < 0.0001)] whereas neither SBP nor UNaV changed in WT mice. AT2-null mice had low basal levels of renal interstitial fluid bradykinin (BK), and cyclic guanosine 3', 5'-monophosphate, an index of nitric oxide production, compared with WT mice. In WT mice, dietary sodium restriction or ANG II infusion increased renal interstitial fluid BK, and cyclic guanosine 3', 5'-monophosphate by approximately 4-fold (P < 0.0001) whereas no changes were observed in AT2-null mice. These results demonstrate that the AT2 receptor is necessary for normal physiological responses of BK and nitric oxide to ANG II. Absence of the AT2 receptor leads to vascular and renal hypersensitivity to ANG II, including sustained antinatriuresis and hypertension. These results strongly suggest that the AT2 receptor plays a counterregulatory protective role mediated via BK and nitric oxide against the antinatriuretic and pressor actions of ANG II.
Topics: Angiotensin II; Animals; Blood Pressure; Bradykinin; Cyclic GMP; Diet, Sodium-Restricted; Homozygote; Kidney; Mice; Mice, Knockout; Microdialysis; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Sodium; Time Factors; X Chromosome
PubMed: 10339618
DOI: 10.1073/pnas.96.11.6506 -
Hong Kong Medical Journal = Xianggang... Jun 2002The renin-angiotensin-aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin-converting enzyme inhibitors inhibit... (Review)
Review
The renin-angiotensin-aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin-converting enzyme inhibitors inhibit angiotensin-converting enzyme and have been shown to be effective in many cardiovascular diseases. They should be considered for the treatment of hypertension in patients with heart failure, previous myocardial infarction, diabetes, or proteinuria. There are a number of side-effects associated with angiotensin-converting enzyme inhibitors, especially persistent dry cough. Angiotensin II receptor antagonists (sartans) provide a more specific blockade of the renin-angiotensin-aldosterone system and are associated with fewer side-effects, including cough. Their long-term efficacy and tolerability in the treatment of patients with hypertension has, however, yet to be established. Periodic monitoring of renal function and electrolytes is required in patients treated with an angiotensin-converting enzyme inhibitor or a sartan.
Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cardiovascular Diseases; Diabetic Nephropathies; Humans; Hypertension; Receptors, Angiotensin; Renin-Angiotensin System
PubMed: 12055364
DOI: No ID Found -
European Review For Medical and... Oct 2013To investigate the relationship between expression of the angiotensin II (Ang II) receptors and thyroid hormones in the myocardium of rats with thyrotoxicosis.
AIM
To investigate the relationship between expression of the angiotensin II (Ang II) receptors and thyroid hormones in the myocardium of rats with thyrotoxicosis.
MATERIALS AND METHODS
Forty-four adult male Sprague-Dawley rats were divided into four groups: control group (saline), losartan group (10 mg/kg), thyrotoxicosis group (0.5 mg/kg L-thyroid hormone sodium) and thyrotoxicosis-plus-losartan group (0.5 mg/kg L-thyroid hormone plus 10 mg/kg losartan) and treated intragastrically daily for four weeks. The heart weight (HW), body weight (BW) and HW/BW ratios were determined. The Ang II protein contents in cardiac homogenates and serum were determined by ELISA. The serum concentrations of levothyroxine (T3), trilodothyronine (T4) and thyroid stimulating hormone (TSH) were measured by radioimmunoassay. The expression of angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) were quantified by real-time PCR and Western blotting.
RESULTS
The thyrotoxicosis group had an increased BW/HW and higher cardiac AT1R and AT2R expression compared to controls. AT1R and AT2R expressions significantly reduced in the thyrotoxicosis-plus-losartan group, compared to the thyrotoxicosis group.
CONCLUSIONS
Thyroid hormone upregulated cardiac AT1R and AT2R, leading to cardiac remodeling, which was reversed by losartan. Cardiac damage in thyrotoxic rats may be related to upregulation of the Ang II receptors.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Cardiomegaly; Losartan; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Thyroid Hormones; Thyrotoxicosis
PubMed: 24142609
DOI: No ID Found -
The Journal of Biological Chemistry Jun 1995The molecular interaction involved in the ligand binding of the rat angiotensin II receptor (AT1A) was studied by site-directed mutagenesis and receptor model building....
The molecular interaction involved in the ligand binding of the rat angiotensin II receptor (AT1A) was studied by site-directed mutagenesis and receptor model building. The three-dimensional structure of AT1A was constructed on the basis of a multiple amino acid sequence alignment of seven transmembrane domain receptors and angiotensin II receptors and after the beta 2 adrenergic receptor model built on the template of the bacteriorhodopsin structure. These data indicated that there are conserved residues that are actively involved in the receptor-ligand interaction. Eleven conserved residues in AT1, His166, Arg167, Glu173, His183, Glu185, Lys199, Trp253, His256, Phe259, Thr260, and Asp263, were targeted individually for site-directed mutation to Ala. Using COS-7 cells transiently expressing these mutated receptors, we found that the binding of angiotensin II was not affected in three of the mutations in the second extracellular loop, whereas the ligand binding affinity was greatly reduced in mutants Lys199-->Ala, Trp253-->Ala, Phe259-->Ala, Asp263-->Ala, and Arg167-->Ala. These amino acid residues appeared to provide binding sites for Ang II. The molecular modeling provided useful structural information for the peptide hormone receptor AT1A. Binding of EXP985, a nonpeptide angiotensin II antagonist, was found to be involved with Arg167 but not Lys199.
Topics: Amino Acid Sequence; Angiotensin II; Animals; Binding Sites; Cells, Cultured; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Rats; Receptors, Angiotensin
PubMed: 7775462
DOI: 10.1074/jbc.270.23.14024 -
European Journal of Pharmacology Nov 1999The angiotensin II type 1 (AT(1)) receptor plays a pivotal role in the regulation of blood pressure and electrolyte balance, and is involved in the control of specific... (Comparative Study)
Comparative Study
The angiotensin II type 1 (AT(1)) receptor plays a pivotal role in the regulation of blood pressure and electrolyte balance, and is involved in the control of specific ingestive behaviours. Irbesartan (SR 47436/BMS 186295) is a recently developed angiotensin AT(1) receptor antagonist, chemically described as 2-butyl-3-([2'-¿1H-tetrazol-5-yl¿biphenyl-4-yl]methyl)-1, 3-diazaspiro (4,4)non-1-en-4-one. Irbesartan displays higher affinity for its target receptor than other similar antagonists. In radioligand binding assays performed on membranes from WB-Fischer 344 (WB) rat liver epithelial cells, irbesartan was able to displace [125I]angiotensin II with a K(i) of 4.05 nM as compared to losartan (DuP 753) and tasosartan (WAY 126756), which had K(i) values of 25.2 nM and 46.6 nM, respectively. Similarly, in functional assays, irbesartan exhibited the highest functional potency to block angiotensin II-induced inositol trisphosphate (IP(3)) turnover. The improved affinity of irbesartan for the angiotensin AT(1) receptor does not coincide with a concomitant increase in affinity for the angiotensin AT(2) receptor, as irbesartan and losartan exhibited the same low potency to displace [125I]angiotensin II in radioligand binding assays performed on membranes from PC-12w cells. In binding assays performed on peripheral tissues in rat, irbesartan bound to the angiotensin AT(1) receptor expressed in liver, adrenal, kidney and pituitary with an overall affinity closely approaching that of the high affinity peptidic antagonist [Sar(1), Ile(8)]angiotensin II. Due to the higher affinity of irbesartan over other similar antagonists for the angiotensin AT(1) receptor in many tissues and its greater potency to block receptor activation, irbesartan may be quite useful in the study of the angiotensin AT(1) receptor and its role in controlling ingestive behaviours and, furthermore, shows great potential to improve the treatment of hypertension and other cardiovascular disease states.
Topics: Adrenal Glands; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Binding, Competitive; Biphenyl Compounds; Cells, Cultured; Dose-Response Relationship, Drug; Iodine Radioisotopes; Irbesartan; Kidney; Liver; Losartan; Male; PC12 Cells; Pituitary Gland; Pyrimidines; Radioligand Assay; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Signal Transduction; Tetrazoles
PubMed: 10611423
DOI: 10.1016/s0014-2999(99)00662-7