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)

Local factors, such as prostaglandins (PGs), nitric oxide (NO), and endothelins (ETs), produced in the immediate vicinity of juxtaglomerular (JG) cells can exert significant effects on renin secretion and renin gene expression. PGE2, as the main renotubular PG, and PGI2, as the main endothelial prostanoid, both stimulate renin secretion and renin gene expression by activating cAMP formation in JG cells. Although the direct effect of NO on JG cells is less clear, its overall effect in vivo seems to be to stimulate the renin system. Evidence is emerging that stimulation by NO is related to the cAMP pathway, and cGMP-induced inhibition of cAMP-phosphodiesterase III (PDE-III) may mediate this effect. ETs, on the other hand, appear to inhibit the renin system, in particular in those pathways activated by cAMP, acting via Ca2+- and protein kinase C-related mechanisms. There is increasing evidence that both NO and PGs could be involved in the physiological regulatory mechanisms by which salt intake affects the renin system.
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PMID:Control of the renal renin system by local factors. 973 59

-The influence of intracellular administration of angiotensin II (Ang II) on the inward calcium current (ICa) was investigated in single myocytes isolated from adult rat ventricle. Comparative studies were also made in ventricular cells of Golden hamsters. The ICa was measured in single cells using the whole-cell voltage clamp configuration. The results indicated that Ang II (10(-8) mmol/L) dialyzed into the rat myocytes reduced the peak ICa by 35+/-5.5% (n=20; P<0.05). Losartan (10(-7) mmol/L) added to the bath did not suppress the effects of Ang II, indicating that the peptide is acting intracellularly. Moreover, the intracellular dialysis of losartan (10(-6) mmol/L) or [Sar1Val5Ala8] Ang II (10(-6) mmol/L) did not change the effect of Ang II. Stimulation of ICa by exogenous cAMP or inhibition of protein kinase C did not alter the effect of Ang II on ICa. Zaprinast (100 micromol/L), an inhibitor of cGMP phosphodiesterase, when added to the bath solution increased appreciably the effect of Ang II on ICa (P<0.05). In ventricular myocytes of Golden hamsters, in which Ang II has a positive inotropic action, the intracellular administration of Ang II (10(-8) mmol/L) increased ICa by 36+/-2.4% (n=20; P>0.05). The effect of the peptide was not altered by the intracellular administration of losartan (10(-6) mmol/L), by [Sar1Val5Ala8] Ang II (10(-6) mmol/L), or by the inhibitor of protein kinase A. The inhibition of protein kinase C, however, prevented the effect of Ang II ICa in the hamster myocytes. The results particularly suggest that the activation of the cardiac renin-angiotensin system regulates ICa and myocardial contractility, an effect that varies with the species.
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PMID:Intracellular angiotensin II regulates the inward calcium current in cardiac myocytes. 985 60

Renin secretion at the level of renal juxtaglomerular cells appears to be controlled mainly by classic second messengers such as Ca2+, cyclic AMP and cyclic GMP, which in turn exert their effects through oppositely acting protein kinases and probably also by affecting the activity of ion channels in the plasma membrane. Thus, protein kinase A stimulates renin secretion, whilst protein kinase C and protein kinase G II inhibit renin secretion. Moreover, Cl- channels could be involved in the mediation of the inhibitory action of Ca2+ on renin secretion. This review summarizes our present knowledge about the possible actions of these kinases in renal juxtaglomerular cells and considers pathways in the organ control of renin secretion.
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PMID:Cellular control of renin secretion. 988 34

Mechanical stretch is an initial factor for cardiac hypertrophy in response to haemodynamic overload (high blood pressure). Stretch of cardiomyocytes activates second messengers such as phosphatidylinositol, protein kinase C, Raf-1 kinase and extracellular signal-regulated protein kinases (ERKs), which are involved in increased protein synthesis. The cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy. Angiotensin II increases the growth of cardiomyocytes by an autocrine mechanism. Angiotensin II-evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, angiotensin II activates ERKs through a pathway including the Gbetagamma subunit of Gi protein, Src family tyrosine kinases, Shc, Grb2 and Ras, whereas Gq and protein kinase C are important in cardiac myocytes. In addition, mechanical stretch enhances the endothelin-1 release from the cardiomyocytes. Further, the Na+ -H+ exchanger mediates mechanical stretch-induced Raf-1 kinase and ERK activation followed by increased protein synthesis in cardiomyocytes. Not only mechanical stress, but also neurohumoral factors induce cardiac hypertrophy. The activation of protein kinase cascades by norepinephrine is induced by protein kinase A through beta-adrenoceptors as well as by protein kinase C through alpha-adrenoceptors.
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PMID:Signalling pathways for cardiac hypertrophy. 988 20

Angiotensin II (AngII) exerts powerful effects on the renal microcirculation to influence a variety of functions. This review summarizes some of the major findings over the past 10 years as they elucidate the multiple roles that AngII plays in the regulation of whole kidney blood flow, perfusion of cortical and medullary regions, and renal autoregulation. Topics of discussion include localization of AngII receptor types and subtypes in the renal vasculature, action of AngII on vascular smooth muscle cells of the afferent and efferent arterioles, and intracellular signaling pathways. Within the microvasculature, AngII causes potent constriction in both the afferent and efferent arterioles, with responses modulated by paracrine and autocrine factors of endothelial and macula densa origins. With regard to renal autoregulatory mechanisms consisting of the myogenic response and the tubuloglomerular feedback mechanism, the myogenic response appears to operate independent of the renin-angiotensin system. On the other hand, tubuloglomerular feedback activity is often directly proportional to concentrations of AngII, especially in high renin states. Of the two types defined to date, the AT1 is the predominant receptor in the adult rat kidney mediating the vascular effects of AngII. AT2 receptor is highly expressed in the fetal kidney and is important for renal development, but is very weakly expressed in adult animals. Nevertheless, AT2 receptors may mediate vasodilation under certain conditions. The signaling transduction pathways for AT1 receptors include Gq/11-protein and protein kinase C activation. AngII causes constriction of the afferent arteriole primarily by stimulation of calcium entry via voltage-sensitive, L-type channels, whereas AngII effects on the efferent arteriole are due to calcium release from intracellular stores and calcium entry through voltage-independent calcium entry channels. Future experiments should contribute to a more in-depth understanding of the modulation of AngII effects by other vasoactive agents and interactions between different second-messenger signaling pathways in health and disease.
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PMID:Actions of angiotensin II on the renal microvasculature. 989 56

Angiotensin II (AngII) resulting as the end product of a proteolytic cascade initiated by renin inhibits the secretion of renin in the sense of a negative feedback. A direct effect of AngII on renal juxtaglomerular epithelioid cells as the main source of renin secretion is mediated via AngII-AT1 receptors and involves calcium-dependent reactions. These reactions may comprise activation of protein kinase C and activation of chloride channels.
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PMID:Regulation of renin secretion by angiotensin II-AT1 receptors. 989 57

In an in vivo study, spontaneously hypertensive rats (SHR) were treated with an angiotensin II (Ang II) type 1 receptor antagonist of candesartan or hydralazine. Untreated SHR progressively developed severe hypertension, and treatment with candesartan or hydralazine decreased blood pressure. Candesartan reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine slightly prevented an increase in LV wall thickness, but did not exert a significant reduction on other parameters. In an in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes. Stretching cardiomyocytes activated second messengers such as protein kinase C, Raf-1 kinase, and mitogen-activated protein (MAP) kinase, increasing protein synthesis, enhancing endothelin (ET)-1 release, activating the Na+/H+ ion exchanger. Moreover, pretreatment with candesartan diminished an increase in phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. This suggests that the cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy and that Ang II increases the growth of cardiomyocytes by an autocrine mechanism. Finally, we examined the signalling pathways leading to MAP kinase activation both in cardiac myocytes and in cardiac fibroblasts. Ang II-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts, Ang II activated MAP kinase through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein kinase C were important in cardiac myocytes.
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PMID:Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress. 1007 20

Immune mechanisms and the renin-angiotensin system are implicated in preeclampsia. We investigated 25 preeclamptic patients and compared them with 12 normotensive pregnant women and 10 pregnant patients with essential hypertension. Antibodies were detected by the chronotropic responses to AT1 receptor-mediated stimulation of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists. Immunoglobulin from all preeclamptic patients stimulated the AT1 receptor, whereas immunoglobulin from controls had no effect. The increased autoimmune activity decreased after delivery. Affinity-column purification and anti-human IgG and IgM antibody exposure implicated an IgG antibody directed at the AT1 receptor. Peptides corresponding to sites on the AT1 receptor's second extracellular loop abolished the stimulatory effect. Western blotting with purified patient IgG and a commercially obtained AT1 receptor antibody produced bands of identical molecular weight. Furthermore, confocal microscopy of vascular smooth muscle cells showed colocalization of purified patient IgG and AT1 receptor antibody. The protein kinase C (PKC) inhibitor calphostin C prevented the stimulatory effect. Our results suggest that preeclamptic patients develop stimulatory autoantibodies against the second extracellular AT1 receptor loop. The effect appears to be PKC-mediated. These novel autoantibodies may participate in the angiotensin II-induced vascular lesions in these patients.
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PMID:Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. 1019 66

This study aimed to identify the intracellular signaling pathway in angiotensin II (Ang II)-induced upregulation of plasminogen activator inhibitor type 1 (PAI-1) mRNA expression in cultured rat glomerular mesangial cells, and to examine the interaction between Ang II and TGF-beta signaling. Ang II-induced upregulation of PAI-1 mRNA expression was prevented by a protein kinase C (PKC) inhibitor, bisindorylmaleimide I. While phorbol 12-myristate 13-acetate (PMA) upregulated the PAI-1 mRNA expression, a calcium ionophore, ionomycin, had little effect. Mesangial cells pretreated with PMA for 24 h to downregulate PKC demonstrated attenuated response to Ang II. A protein tyrosine kinase inhibitor, genistein, completely blocked both Ang II- and PMA-induced PAI-1 mRNA expression. Transforming growth factor-beta1 (TGF-beta1) alone induced the expression, and in the presence of Ang II, TGF-beta1 superinduced PAI-1 mRNA expression to a higher extent. Both bisindorylmaleimide I and genistein suppressed the Ang II plus TGF-beta1-induced PAI-1 mRNA upregulation to the basal level, while downregulation of PKC attenuated the synergistic upregulation of PAI-1 mRNA expression to the level comparable to TGF-beta1 alone. These data suggest that, in rat mesangial cells, (1) PKC and protein tyrosine kinase(s) are involved in the Ang II signaling cascade, (2) protein tyrosine kinase(s) works downstream from PKC in the cascade, and (3) there is an interaction between the Ang II and TGF-beta signal pathways downstream from PKC. In in vivo settings, local activation of renin-angiotensin and TGF-beta systems in the glomeruli may synergistically augment PAI-1 expression, promote mesangial matrix accumulation and progression of glomerular injury.
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PMID:Association of TGF-beta signaling in angiotensin II-induced PAI-1 mRNA upregulation in mesangial cells: role of PKC. 1020 1

Biological and mechanical stressors such as ischemia, hypoxia, cellular ATP depletion, Ca2+ overload, free radicals, pressure and volume overload, catecholamines, cytokines, and renin-angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury. Adenosine, a degradative substance of ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and chronic heart failure. For example, when brief periods of myocardial ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the enzyme responsible for adenosine release, ie, ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase reduced the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that protein kinase C is responsible for the activation of ecto-5'-nucleotidase. Protein kinase C phosphorylated the serine and threonine residues of ecto-5'-nucleotidase. Therefore, we suggest that adenosine produced via ecto-5'-nucleotidase gives cardioprotection against ischemia and reperfusion injury. Also, we found that plasma adenosine levels are increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic heart failure, which may explain the increases in adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma adenosine levels due to either dipyridamole or dilazep reduces the severity of chronic heart failure. Thus, we suggest that endogenous adenosine is also beneficial in chronic heart failure. We propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may be useful for the treatment of either ischemic heart diseases or chronic heart failure.
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PMID:Adenosine and cardioprotection in the diseased heart. 1047 69


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