Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic and/or locally produced angiotensin II stimulates salt and water reabsorption in the renal proximal tubule. In vivo, dopamine (DA) may serve as a counterregulatory hormone to angiotensin II's acute actions on the proximal tubule. We examined whether dopamine modulates AT1 receptor expression in cultured proximal tubule cells (RPTC) expressing DA1 receptors. Dopamine decreased basal RPTC AT1 receptor mRNA levels by 67 +/- 7% (n = 10; P < 0.005) and decreased 125I-angiotensin II binding by 41 +/- 7% (n = 4; P < 0.05). The DA1-specific agonist, SKF38393 decreased basal AT1 receptor mRNA levels (65 +/- 5% inhibition; n = 5; P < 0.025), and the DA1-specific antagonist, SCH23390 reversed dopamine's inhibition of AT1 receptor mRNA expression (24 +/- 10% inhibition; n = 8; NS) and angiotensin II binding (5 +/- 15%; n = 4; NS). DA2-specific antagonists were ineffective. In rats given L-DOPA in the drinking water for 5 d, there were decreases in both proximal tubule AT1 receptor mRNA expression (80 +/- 5%; n = 6; P < 0.005) and specific [125I] Ang II binding (control: 0.74 +/- 0.13 fmol/mg pro vs. 0.40 +/- 0.63 fmol/mg pro; n = 5; P < 0.05). In summary, dopamine, acting through DA1 receptors, decreased AT1 receptor expression in proximal tubule, an effect likely mediated by increased intracellular cAMP levels. Local dopamine production also led to decreased AT1 receptor expression, suggesting dopamine may reset sensitivity of the proximal tubule to angiotensin II.
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PMID:Dopamine decreases expression of type-1 angiotensin II receptors in renal proximal tubule. 867 85

To define the signal transduction pathway linked to the cardiac angiotensin II (AII) receptor type 2 (AT2-R), cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts. Protein kinase C (PKC) activity was assayed in membrane and cytosolic fractions of the cardiac cells. AII significantly (p < 0.05) increased membrane PKC activity and decreased cytosolic PKC activity, in a concentration-dependent manner, suggesting a translocation of PKC from cytosol to membrane. AT2-R blockade by its antagonist, PD123319, produced a dose-dependent antagonism of AII-induced activation of PKC. PD123319, at 10(-6) M or greater concentrations, completely antagonized AII-induced PKC activation, in contrast to a small reduction in PKC activity by the AII receptor type 1 (AT1-R) antagonist losartan. Isoproterenol-induced cAMP generation was significantly (p < 0.05) blunted by AII. AT2-R blockade did not alter AII-induced reduction of beta-adrenoceptor-mediated increases in cAMP generation, in contrast with AT1-R blockade, which abolished AII-induced reduction of beta-adrenergic-mediated cAMP production. These data suggest that AT2 receptors have a previously unrecognized, role in the heart, namely, coupling AII to PKC.
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PMID:The angiotensin II subtype 2 (AT2) receptor is linked to protein kinase C but not cAMP-dependent pathways in the cardiomyocyte. 872 23

The renal vasculature of young spontaneously hypertensive rats (SHR) responds to angiotensin II (ANG II) with exaggerated vasoconstriction, due in part to defective buffering by the adenosine 3',5'-cyclic monophosphate (cAMP) pathway. In vitro studies suggest greater activation of phospholipase C and protein kinase C (PKC) in cultured mesangial cells and vascular smooth muscle cells. The present studies evaluated the role of PKC activation in renal vascular responses to ANG II receptor activation and the relative contributions in SHR vs. Wistar-Kyoto control rats (WKY). Renal blood flow was measured in 8-wk-old anesthetized SHR and WKY pretreated with indomethacin. ANG II (2 ng) injection into the renal artery produced a transient 45-50% maximum reduction of renal blood flow in both rat strains. Intrarenal infusion of either staurosporine or chelerythrine into the renal artery effectively attenuated the vasoconstriction elicited by ANG II in a dose-dependent manner, with maximum inhibition of 60-70%. The PKC inhibitory effects were significant and independent of strain. Coadministration of the PKC inhibitors produced maximal inhibition similar to that observed with one agent, suggesting action via a common pathway. In other studies, the linkage of the PKC pathway to the AT1 receptor was evaluated using sub and maximal doses of losartan to antagonize 50-80% of ANG II-induced vasoconstriction. The same degree of inhibition was observed when a PKC inhibitor was coadministered with losartan. These findings support the views that the PKC system is a major intracellular signaling pathway coupled to the AT1 receptor in renal resistance vessels and that PKC activation is involved to similar degrees in the renal vasoconstriction elicited by ANG II in young WKY and SHR. Exaggerated vascular reactivity to vasoconstrictor agents in genetically hypertensive animals is probably due to a defect in cAMP generation in the presence of a normally operating PKC pathway.
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PMID:Role of protein kinase C in angiotensin II-induced renal vasoconstriction in genetically hypertensive rats. 876 13

In the present study, 3-day treatment of nondifferentiated NG108-15 cells with 100 nM angiotensin II (Ang II) induces morphological differentiation of neuronal cells characterized by the outgrowth of neurites. These morphological changes are correlated with an increase in the level of polymerized tubulin and in the level of the microtubule-associated protein, MAP2c. Mediation by the AT2 receptor may be inferred since: (a) these cells contain only AT2 receptors; (b) the effects are mimicked by CGP 42112 (an AT2 receptor agonist); (c) they are not suppressed by the addition of DUP 753 (an AT1 receptor antagonist); and (d) are abolished by co-incubation with PD 123319 (an AT2 receptor antagonist). Application of Ang II in dibutyryl cAMP-differentiated cells (which contain both types of receptors) induces neurite retraction, an effect mediated by the AT1 receptor. These results indicate that the AT2 receptor of Ang II induces neuronal differentiation, which is initiated through an increase in the levels of MAP2c associated with tubulin. Moreover, our results demonstrate that the AT1 receptor inhibit the process of differentiation induced by dibutyryl cAMP, whereas the AT2 receptors potentiate this effect, illustrating negative cross-talk interaction between the two types of Ang II receptors.
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PMID:Angiotensin II induction of neurite outgrowth by AT2 receptors in NG108-15 cells. Effect counteracted by the AT1 receptors. 879 47

The aim of our study was to determine the second messenger systems for angiotensin II in the rat median eminence. Angiotensin II AT1 receptors are highly expressed in the median eminence and binding is selectively inhibited by the guanine nucleotide GTP gamma S, indicating possible coupling to G-proteins. In male rats, angiotensin II increased phosphatidylinositol hydrolysis about 45% over basal values, with an EC50 of about 2.7 nM. This effect was antagonized by 10 microM losartan, the selective AT1 antagonist, but not by the AT2 competitor PD 123319. Conversely, angiotensin II, 1 microM, did not alter basal or forskolin-stimulated cAMP production, and failed to influence cGMP production. These results support a role for angiotensin II, through stimulation of AT1 receptors and increased phosphatidylinositol hydrolysis, in the median eminence. Angiotensin II increased the phosphatidylinositol hydrolysis not only in male rats but also in ovariectomized rats, with or without estrogen-progesterone replacement. However, angiotensin II (up to 1 microM) failed to increase the phosphatidylinositol hydrolysis in randomly selected intact female rats. Estrogen treatment did not alter the number or affinity of median eminence AT1 receptors in ovariectomized rats. The increase in phosphatidylinositol hydrolysis resulting from stimulation of median eminence AT1 receptors appears to be sexually dimorphic, but hormonal manipulations failed to point to a role for reproductive hormones in this phenomenon.
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PMID:Stimulation of angiotensin II AT1 receptors in rat median eminence increases phosphoinositide hydrolysis. 882 29

The regulation of the AT1 receptor gene was studied in neonatal cardiomyocytes and fibroblasts in vitro. Incubation with angiotensin II (Ang II) resulted in a time-dependent and dose-dependent decrease in AT1 mRNA levels in both cardiomyocytes and fibroblasts. Coincubation with Ang II and the specific AT1 antagonist losartan prevented the decrease in AT1 mRNA whereas the AT2 antagonist PD123319 was ineffective in preventing the decrease in AT1 mRNA. Because Ang II is known to decrease cAMP levels in cardiomyocytes, the role of cAMP in the regulation of the AT1 gene was examined. Treatment with the adenylyl cyclase stimulant forskolin or the cAMP stereoisomer Sp-cAMPS increased AT1 mRNA levels or prevented the Ang II mediated decrease in AT1 mRNA levels. The role of calcium in the regulation of the AT1 gene was determined by incubation with the calcium ionophores A23187 and ionomycin (0.0625-1 microM) which resulted in a profound, dose-dependent decrease in AT1 mRNA levels. Treatment with BAPTA, an intracellular chelator of calcium, prevented the Ang II-mediated decrease in AT1 mRNA. Therefore Ang II is a potent negative regulator of the AT1 gene in cardiomyocytes and fibroblasts via the AT1 receptor. This Ang II mediated decrease in AT1 mRNA is mediated by two complementary mechanisms involving cAMP and intracellular calcium.
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PMID:AT1 receptor gene regulation in cardiac myocytes and fibroblasts. 887 82

Because angiotensin II (Ang II) has been found at high concentrations in the proximal tubule fluid and because tubular brush border membranes exhibit a marked capacity for degrading Ang II, we thought it of interest to examine the binding sites for Ang II (3-8) (referred to as Ang IV), a metabolite of Ang II, downstream in the nephron. We studied the binding of [125I]-Ang IV and also of [125I]-Sar1, Ala8, Ang II to SV-40 transformed human collecting duct cell (HCD) membranes. No specific binding site for [125I]-Sar1, Ala8, Ang II and no Ang II-dependent cytosolic calcium response could be observed. Moreover, no signal for the human type I Ang II receptor (hAT1) mRNA was present in HCD cells. In contrast, [125I]-Ang IV bound specifically to HCD cell membranes. Mean Kd and Bmax values derived from saturation binding studies were 5.6 +/- 2.0 nM and 1007.6 +/- 140.2 fmol/mg protein, respectively. The rank order of affinity for competitive Ang II-related peptides was: Ang IV > Ang III > Ang II > Ang II (4-8) > Ang II (1-7). [125I]-Ang IV binding was not modified by nonpeptide AT1 (losartan) or AT2 (PD123177) antagonists. GTP gamma S and dithiotreitol did not affect [125I]-Ang IV binding. Ang IV stimulated cAMP production by intact HCD cells in the presence of forskolin but did not modify cGMP production or cytosolic calcium concentration. Taken together, these results indicate that HCD cells represent a target site for Ang IV but do not possess Ang II receptors.
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PMID:Evidence for angiotensin IV receptors in human collecting duct cells. 888 69

Regulation of AT1 receptor mRNA expression is an important determinant of angiotensin II-induced steroidogenesis. We have PCR-amplified the bovine adrenal AT1 receptor coding region using primers designed from the published bovine AT1 receptor sequence. This has been used as a probe on Northern blots to detect changes in the levels of AT1 receptor mRNA in primary cultures of bovine zona fasciculata cells in response to activation of several different signal transduction mechanisms in addition to two major adrenal steroid products, cortisol and aldosterone. AT1 receptor mRNA decreased in response to 6hr AII (10 nM) treatment, but returned to basal levels following 48h AII treatment. This effect was mimicked by the phorbol ester PMA (1 microM) and the calcium ionophore A23187 (1 microM), both singly and in combination. Activation of the cAMP pathway by ACTH (1 nM) and 8-bromo-cAMP (0.1 microM) also decreased AT1 receptor mRNA levels. In contrast, both IGF-1 (10 ng/ml) and potassium ions (12 mM) increased the levels of AT1 receptor mRNA. Finally, cortisol (10 microM) but not aldosterone (100 nM) decreased AT1 receptor mRNA. We conclude that the regulation of AT1 receptor mRNA in bovine zona fasciculata cells could involve several different signal transduction systems in addition to adrenocortical steroids themselves.
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PMID:Multiple signal transduction systems regulate angiotensin II type 1 (AT1) receptor mRNA expression in bovine adrenocortical cells. 896 84

Rabbit cortical collecting duct (CCD) cells were immortalized to study angiotensin II (ANG II) signaling in the CCD. Transfected cells retained CCD properties; arginine vasopressin (AVP), prostaglandin E2, and isoproterenol (10(-7) M) all significantly stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production; and parathyroid hormone and calcitonin had no effect on cAMP. Twenty-seven percent of transfected cells bound the beta-intercalated cell marker peanut lectin agglutinin, whereas antibodies against principal cells and alpha-intercalated cells immunolabeled 26% of cells. All cells stained with antibodies to the epithelial cell marker cytokeratin. By contrast, no immunofluorescence was observed with antibodies to smooth muscle myosin, Tamm-Horsfall protein, or factor VIII. Transfected cells demonstrated amiloride-sensitive transepithelial short-circuit current. In transfected cells, radioligand binding assays detected a single class of ANG II receptors (affinity constant = 0.78 nM), and AT1-receptor mRNA was demonstrated by Northern analysis. ANG II (10(-7) M) significantly inhibited AVP-stimulated cAMP production; lower concentrations (10(-10) M) increased phosphoinositide hydrolysis. In summary, we immortalized a rabbit CCD cell line that retains characteristic morphological and hormonal properties. These cells express AT1 receptors, coupled to inhibition of cAMP and to stimulation of phosphoinositide turnover. We postulate that these signaling pathways may mediate effects of ANG II on CCD transport and cell growth.
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PMID:Immortalized rabbit cortical collecting duct cells express AT1 angiotensin II receptors. 899 88

Modulation of ionic Ca2+ currents by dopamine (DA) could play a pivotal role in the control of steroid secretion by the rat adrenal glomerulosa cells. In the present study, we report that DA decreases the T-type Ca2+ current amplitude in these cells. The use of pharmacological agonists and antagonists reveals that this effect is mediated by activation of the D1-like receptors. Modulation by cAMP is complex inasmuch as preincubation of the cells with 8-Br-cAMP or the specific adenylyl cyclase inhibitor, 2',3'-dideoxyadenosine, have no effect per se, but prevent the DA-induced inhibition. The inhibitory effect of DA was abolished by addition of GDPbetaS to the pipette medium but not by pertussis toxin. If a cell is dialyzed with medium containing G alpha(s)-GDP, the inhibitory effect is reduced and cannot be recovered by the addition of GTPgammaS, indicating that the alpha(s) is not involved, but rather the betagamma-subunit. Indeed, DA-induced inhibition was mimicked by G betagamma in the pipette and 8-Br-cAMP in the bath. Similarly, G betagamma release from the activation of the AT1 receptor of angiotensin II did affect the current amplitude only in the presence of 8-Br-cAMP in the bath. The mitogen-activated protein kinase cascade, which can be activated by receptors coupled to Gs, was not involved as shown by the lack of activation of p42mapk by DA and the absence of effect of the mitogen-activated protein kinase inhibitor, PD 098059, on the DA-induced inhibition. Because the binding of G betagamma-subunits to various effectors involves the motif QXXER, we therefore tested the effect of the QEHA peptide on the inhibition of the T-type Ca2+ current induced by DA. The peptide, added to the medium pipette (200 microM), abolished the effect of DA. We conclude that the presence of the G betagamma and an increase in cAMP concentration are both required to inhibit the T-type Ca2+ current in rat adrenal glomerulosa cells.
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PMID:Inhibition of the T-type Ca2+ current by the dopamine D1 receptor in rat adrenal glomerulosa cells: requirement of the combined action of the G betagamma protein subunit and cyclic adenosine 3',5'-monophosphate. 909 2


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