Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (ANG II) was shown to modulate transport in the renal proximal tubule through both inhibition of adenylate cyclase and protein kinase C (PKC) activation. We evaluated the effects of ANG II on adenosine 3',5'-cyclic monophosphate (cAMP) content and Na-H exchange activity (amiloride-sensitive Na influx) in two strains of opossum kidney (OK) cells originating from different sources, OK-VD and OK-RR cells. In OK-VD cells, ANG II inhibited basal and parathyroid hormone (PTH)-induced cAMP generation in a pertussis toxin-sensitive manner and reversed PTH inhibition of Na-H exchange. These effects of ANG II were prevented by PD 123319, a selective nonpeptide antagonist of AT2 receptors. In contrast, DuP 753, which antagonizes selectively AT1 receptors, had no effect. In OK-RR cells, ANG II had no effect on cAMP content and decreased Na-H exchange activity. The effect of ANG II persisted in the presence of PTH but was abolished by PKC downregulation and by DuP 753, but not by PD 123319. In conclusion, two types of ANG II receptors, coupled to distinct signaling pathways, were expressed independently in OK cells originating from two different sources and mediated opposite effects of ANG II on Na-H exchange activity. Those models provide a powerful tool for studying the intracellular steps involved in the tubular effects of ANG II and to evaluate the effect of pharmacological inhibitors of ANG II binding to its receptors.
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PMID:Modulation of Na-H exchange activity by angiotensin II in opossum kidney cells. 133 86

In this study, we investigated the mechanism of angiotensin II (Ang II) induced secretion of plasminogen activator inhibitor-1 (PAI-1) from astroglial cells prepared from 21-day-old rat brain. Competition-inhibition experiments with the use of selective antagonists for Ang II receptor subtypes indicated that astroglial cells contain chiefly Ang II type 1 (AT1) receptors. The interaction of Ang II with AT1 receptors resulted in a time- and concentration-dependent stimulation of PAI-1 gene expression. A maximal, 20-fold induction of PAI-1 messenger RNA (mRNA) steady-state levels was observed with 10 nM Ang II. This effect of Ang II was blocked by DuP753, an AT1 receptor antagonist, but not by PD123177, an AT2 receptor antagonist. Raise in PAI-1 mRNA levels was followed by an elevation in PAI-1 concentration in culture media reaching its maximum after 24 h. Interaction of Ang II with AT1 receptors also resulted in a time- and concentration-dependent stimulation of inositol phospholipid (IP) hydrolysis. A maximal, 3- to 5-fold stimulation of IP hydrolysis was observed with 10 nM Ang II. The time course experiments indicated that Ang II-induced stimulation of IP hydrolysis precedes the stimulation of PAI-1 mRNA. This suggested that activation of phospholipase C, IP hydrolysis system and possibly protein kinase C (PKC) may mediate Ang II's effect on PAI-1 mRNA. Direct stimulation of PKC by phorbol ester, phorbol 12,13-dibutyrate (PDB), resulted in a time- and concentration-dependent elevation of PAI-1 mRNA levels, similar to that caused by Ang II (maximal stimulation of 20-fold with 100 nM PDB for 4 h). This effect was totally blocked by the protein kinase C inhibitor, H7. In addition, Ang II stimulation of PAI-1 mRNA was also blocked by H7. In contrast, Ang II did not elevate PAI-1 mRNA levels in astroglial cultures from neonatal rat brains. However, treatment of neonatal cultures with PDB increased levels of this mRNA species. These observations indicate that the coupling of AT1 receptors with IP hydrolysis and PKC activation may be important for Ang II stimulation of PAI-1 gene expression. The lack of Ang II's effect on PAI-1 mRNA in neonatal astroglia may be explained either by a low coupling efficiency between AT1 receptors and the second messenger system, or by a low AT1 to AT2 receptor level ratio.
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PMID:Angiotensin II stimulation of plasminogen activator inhibitor-1 gene expression in astroglial cells from the brain. 153 91

The effect of angiotensin II (ANG II) on cytosolic free Ca2+ concentration ([Ca2+]i) was studied in cultured neonatal rat ventricular myocytes. [Ca2+]i was estimated in groups of one to three cells by dual-wavelength microfluorometry or in cell populations using conventional fluorometry. ANG II (10(-8) M) produced an acute short-lived increase over the control basal diastolic [Ca2+]i and increased the frequency of the [Ca2+]i transients. The amplitude of the [Ca2+]i transients was decreased to 64.4% of basal values. The effect of ANG II on [Ca2+]i was blocked by the selective AT1 receptor subtype antagonist Du Pont 753 but not by the AT2 antagonist PD 123319. Removal of extracellular Ca2+ or blockade of voltage-gated Ca2+ channels in cells cultured for 5-7 days abolished the [Ca2+]i transients, but only partially diminished the effect of ANG II on [Ca2+]i. Thapsigargin, an inhibitor of sarcoplasmic reticulum Ca(2+)-Mg(2+)-ATPase, reduced or abolished the [Ca2+]i response to ANG II. Phorbol 12-myristate 13-acetate (PMA), 10(-6) and 10(-7) M, also decreased the amplitude of the Ca2+ transients similar to ANG II. Pretreatment with 10(-6) M PMA or 10(-6) M 1-oleoyl-2-acetyl-glycerol (OAG) inhibited the initial rise in [Ca2+]i and the Ca2+ transients. Thus ANG II produces an acute rise in [Ca2+]i which is derived predominantly from sarcoplasmic reticulum intracellular stores. This acute effect is followed by a significant reduction in the amplitude for the Ca2+ transient and may be mediated by activation of protein kinase C.
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PMID:Effect of angiotensin II on cytosolic free calcium in neonatal rat cardiomyocytes. 183 Apr 56

The mechanism by which a novel potent non-peptide angiotensin subtype 1 receptor (AT1) agonist, (5,7-dimethyl-2-ethyl-3-[[2'-[(butyloxycarbonyl) aminosulfonyl]-5'-(3-methoxybenzyl)-[1,1'-biphenyl]-4-yl] methyl]-3H-imidazo [4,5-b] pyridine) (L-163,491), increased pulmonary vascular resistance was investigated in the intact-chest anesthetized cat under conditions of controlled blood flow. Intralobar injections of L-163,491, in doses of 10-300 micrograms i.a., caused dose-related increases in lobar arterial pressure that were partially antagonized by an AT1 receptor antagonist, DuP 532, or by staurosporine, a protein kinase C inhibitor, in doses that antagonized pressor responses to Ang II, but not to the thromboxane A2 mimic, U46619. Responses to L 163491 were not altered by PD 123319, an AT2 receptor antagonist. These data provide support for the hypothesis that vasoconstrictor responses to L 163491 are mediated by the activation of AT1 receptors and the protein kinase C pathway in the pulmonary vascular bed of the intact-chest cat.
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PMID:Responses to a nonpeptide angiotensin receptor agonist, L 163491, in the feline pulmonary vascular bed. 747 24

Human adrenocortical H295R cells express AII receptors which are predominantly of the AT1 but not AT2 subclass. These receptors are functionally coupled to phosphoinositidase C in a manner similar to that seen in fetal human, sheep and bovine adrenocortical cells. Treatment of H295R cells with forskolin or dbcAMP to activate the protein kinase A pathway caused a rapid (maximal by 3 h) and sustained decrease in AT1-R mRNA levels which in turn preceded a time-dependent (maximal by 12 h) and dose-dependent loss of [125I]AII binding and phosphoinositidase C activation on subsequent AII challenge. Thus, both decreased AT1-R mRNA levels and functional receptor expression appear to parallel each other in response to activation of protein kinase A. Activation of the Ca2+/protein kinase C pathways by treatment with AII also caused a rapid (maximal by 3 h) and dose-dependent loss in AT1-R mRNA, but mRNA levels subsequently rose again, approaching control levels by 36 h. Treatment with AII for 48 h had little effect on either [125I]AII binding or the subsequent phosphoinositidase C response. The effect of AII, but not forskolin, was blocked by the presence of cycloheximide. The action of AII on AT1-R mRNA was probably mediated through both protein kinase C and Ca(2+)-sensitive protein kinases as the effect at 4 h was not completely reproduced by phorbol ester alone, but was fully reproduced by a combination of phorbol ester and Ca2+ ionophore. However, increased Ca2+ influx alone, due to treatment with BAYK8644 or elevated extracellular K+, also resulted in a decrease in AT1-R mRNA levels. Thus in the H295R cell, control of AT1-R expression appears to be complex, being achieved at least in part through control of the level of AT1-R mRNA by multiple independent signaling pathways including protein kinase A, protein kinase C and Ca2+.
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PMID:Hormonal regulation of angiotensin II type 1 receptor expression and AT1-R mRNA levels in human adrenocortical cells. 758 78

Bovine fasciculata cells in culture (BAC) express both AT1 and AT2 angiotensin receptors. The role and signaling pathways of this latter receptor are still the subject of debate. We found that in BAC stimulation of cortisol (F) production by angiotensin II (A II) is accounted for by both receptor subtypes. We have investigated the potential AT2 signalling pathways involved in this response. As previously described in other cells, we found this receptor to mediate inhibition of ANP stimulated cGMP production through a phosphodiesterase independent pathway. This phenomenon does however not appear to be involved in cortisol production as this response was not affected by the addition of 8-Br-cGMP or ANP. It was however abolished after down-regulation of PKC by phorbol esters, but not by Gi inhibition with pertussis toxin. Moreover and as opposed to the AT1 mediated response, AT2 receptor stimulation potentiated K+ induced F production. In conclusion, these observations suggest that the AT2 pathway which mediates F production requires intact PKC and might involve a Gi independent stimulation of Ca++ or K+ channels.
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PMID:Stimulation of cortisol production through angiotensin AT2 receptors in bovine fasciculata cells. 758 79

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
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PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

Angiotensin II (AngII) is a hormone that alters contractility as well as myocyte growth in heart. Since many hormones that regulate cardiac contractility have also been found to modulate intracellular pH (pHi) the goal of this study was to determine if AngII altered pHi in cultured neonatal rat ventricular myocytes. Changes in pHi were monitored in single cells using the fluorescent pH indicator carboxy-seminaphthorhodafluor-1. Application of 100 nM AngII resulted in a rapid, receptor-mediated alkalinization of 0.08 +/- 0.02 pH unit. The Na+/H+ exchanger was not involved since the response was HCO3(-)-dependent and amiloride-insensitive. Ammonia rebound experiments showed AngII increased the initial rate of recovery from an imposed acid load by 3.15-fold and showed that the hormone led to the selective activation of the Na+/HCO3- symport. In contrast, phorbol ester activation of protein kinase C led to the selective activation of Na+/H+ antiport in these cells. Pharmacological studies showed that the alkalinization was independent of the AngII receptor subtype 1 (AT1) phosphoinositide signaling path. In contrast, AngII activation of the symport was blocked by nanomolar AT2 receptor antagonist PD 123319. Superfusion of the myocytes with exogenous arachidonic acid (5 microM) mimicked the AngII-mediated alkalinization, further suggesting that the AT2 signaling pathway underlies the response. In summary, while most of the known actions of AngII in heart are mediated through AT1 receptors, activation of the Na+/HCO3- symport occurs through a distinct alternative path that is likely related to fatty acid production.
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PMID:Angiotensin II activates the Na+/HCO3- symport through a phosphoinositide-independent mechanism in cardiac cells. 765 18

The two forms of angiotensin II (Ang II) receptors, AT1 and AT2 subtypes, have been demonstrated in many other cells beside the anterior pituitary cells. Attempting to investigate the subtype(s) of Ang II receptors implicated in the multiple transduction mechanisms involved in Ang II stimulation of prolactin (PRL) release by lactotropes, we studied the effect of selective nonpeptidergic Ang II antagonists on the PRL release, adenylate cyclase (AC), and phospholipase C activities. In intact cells, the AT1 antagonist DuP753 blocked Ang II-induced PRL release, reversed in a dose dependent manner Ang II-evoked inositol phosphates production, and inhibited completely the PLC and protein kinase C (PKC) dependent cAMP accumulation induced by Ang II. In membrane preparations, the Ang II receptors were negatively coupled to AC. The AT1 antagonist blocked in a dose dependent manner the inhibitory effect of Ang II on cAMP production. In intact cells, the negative coupling of Ang II receptor with AC was observed only when PKC was down regulated by long term 12-O-tetradecanolylphorbol-13-acetate pretreatment. Ang II was able to inhibit vasoactive intestinal peptide-induced cAMP accumulation, a response which was also prevented by DuP753. The different coupling of Ang II receptor described above implicated only the AT1 type receptor since the AT2 antagonists (PD123177 and PD123319) were ineffective at any doses tested (10(-8) to 10(-5) M). The obtained results indicate that the regulation of PRL secretion involves the AT1 receptor subtype and that this receptor might be coupled to multiple effectors.
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PMID:Angiotensin II effects on second messengers involved in prolactin secretion are mediated by AT1 receptor in anterior pituitary cells. 770 34

With the development of subtype specific angiotensin II (Ang II) receptor antagonists and their introduction into the treatment of heart failure and hypertension, the regulation of the Ang II receptor with its subtypes AT1 and Ang T2 gains clinical importance. In cell cultures, the number of surface AT1 is clearly down-regulated by Ang II exposure. Down-regulation can be due to reversible internalization, to phosphorylation and to reduced synthesis and involves protein kinase C and phospholipase C mediated pathways. In this respect, the AT1 behaves as a typical G-protein coupled receptor. Aldosterone, cAMP, norepinephrine and extracellular glucose concentrations can contribute to AT1 regulation. There are very few data regarding the regulation of the subtype AT2, indicating modulation by a number of growth factors and by Ang II. In whole animal models receptor regulation deviates partially from cell cultures. In the rat, the two subtypes AT1A and AT1B are differentially regulated and the expression of subtypes is organ specific. In most experiments, including our own experiences, the AT1, in the adrenals was up-regulated by Ang II infusion and down-regulated by angiotensin converting enzyme inhibitors (ACEI) or Ang II receptor antagonists. Differing effects were observed in other organs. In humans, a number of studies seeking an association between Ang II levels, Ang II receptor regulation and physiological events have been conducted in platelets. In pregnant women, a negative correlation between plasma Ang II levels and Ang II binding and an association between receptor regulation and pregnancy-induced hypertension has been described.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the angiotensin receptor subtypes in cell cultures, animal models and human diseases. 771 21


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