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 acts on the cardiac fibroblast to produce a mitogenic response. Nitric oxide and N-acetylcysteine have been used to determine if oxidative stress influenced the effects of angiotensin II on the cardiac fibroblast. Angiotensin II activated the mitogen-activated protein kinases designated extracellular signal-regulated kinases within 5 min by interacting with the AT1 receptor. This activation was completely independent of protein kinase C and was inhibited when farnesylation was blocked, implicating Ras involvement. Pretreatment of cardiac fibroblasts with either N-acetylcysteine for 8 h or nitric oxide for 10 min suppressed this activation by angiotensin II in a dose-dependent manner. However, when both agents were added, inhibition was essentially complete. This combined effect of N-acetylcysteine and nitric oxide to block ERKs activation also was found if the activity was stimulated by either another growth factor (platelet-derived growth factor) or by the addition of phorbol ester, suggesting the effect was not limited to the receptor site alone. The results are consistent with the hypothesis that hormonal activation of mitogenic steps such as ERKs is influenced by increased oxidative stress, which is reduced by the combined effects of N-acetylcysteine and nitric oxide.
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PMID:Nitric oxide and N-acetylcysteine inhibit the activation of mitogen-activated protein kinases by angiotensin II in rat cardiac fibroblasts. 983 56

Angiotensin II is a key element in regulating the volume of extracellular liquid. It acts indirectly through aldosterone secretion by adrenals and directly on the renal tubule too: It regulates luminal Na+/H+ antiporters (NHE3 and possibly NHE2) after binding to membrane AT1 receptors located both on the basolateral and on the apical side of the cells. The main site of Ang II action is proximal tubule, mainly the S1 segment which has a high level of AT1 receptors. Circulating Ang II concentrations (10(-12) to 10(-10) M), increased NaCl, water and NaHCO3 reabsorption via NHE3 in the proximal tubule. There is also a synthesis of Ang II within the cells of proximal tubule, which is secreted within the lumen where the physiological concentration is stable 10(-8) M, i.e. 100 to 1000 times higher than the circulating concentration. Luminal ANG II originating from kidney has a physiological autocrine function on NaCl, water and probably NaHCO3 reabsorption, since inhibiting Ang II synthesis, by conversion enzyme inhibition, or effect, by AT1 receptor antagonists, induces a reduction of proximal tubule reabsorption. The stimulatory effects of circulating and intrarenal Ang II seem to be explained by protein kinase C stimulation and possibly by a reduction of cAMP production or by a stimulation of a non-receptor tyrosine kinase. When pharmacological doses of Ang II (> 10(-8) M) are applied in the peritubular or the luminal medium of isolated microperfused proximal tubule in vitro, a paradoxical inhibition of NHE3 was observed. These effects appear to involve arachidonic acid metabolites through the cytochrome P450 pathway and possibly a rise in cytosolic free Ca++. The physiological significance of these supraphysiological effects are unknown.
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PMID:[Effect of angiotensin ii on Na+/H+ exchangers of the renal tubule]. 985 78

In C9 (Clone 9) liver cells, angiotensin 11 increased the intracellular Ca2+ content, inositol phosphate production and c-fos mRNA expression. Other angiotensins were also active with the order of potency being angiotensin II = angiotensin III >> angiotensin I > angiotensin IV. Losartan, but not PD 123177 (1-(4-amino-3-methyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imida zo [4,5c]pyridine-6-carboxylic acid), blocked the effects of angiotensin II. Pertussis toxin did not alter these actions of angiotensin II. These data indicate that the effects were mediated through angiotensin AT1 receptors involving pertussis toxin-insensitive G-proteins. Phorbol myristate acetate was also able to increase c-fos mRNA expression. The action of angiotensin II was consistently greater than that of the active phorbol ester. Staurosporine but not genistein inhibited this effect of angiotensin II. Angiotensin II- and phorbol myristate acetate-induced proto-oncogene mRNA expression was attenuated in cells incubated overnight with the active phorbol ester, which suggests a major role of protein kinase C.
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PMID:Angiotensin AT1 receptors in Clone 9 rat liver cells: Ca2+ signaling and c-fos expression. 987 76

Previous studies have documented that the vasoactive agonist angiotensin II (AngII) directly affects proximal tubular sodium-bicarbonate reabsorption in a biphasic manner, whereby picomolar concentrations promote reabsorption and nanomolar concentrations have the converse effect. Although it is generally agreed that the AT1 receptor subtype mediates AngII-induced sodium-bicarbonate reabsorption primarily through adenylate cyclase, the receptor subtype mediating natriuresis is less well defined. Using mouse proximal tubular cells, this study documents AT1-dependent enhancement (candesartan-inhibitable) of bicarbonate reabsorption and AT2-induced (PD123319- and CGP42112A-inhibitable) decrement of bicarbonate absorption. The signaling mechanisms were examined in rabbit proximal tubule cells in culture. The AT2 signaling involves G protein beta- and gamma-mediated phospholipase A2 activation, arachidonic acid release, and downstream events linked to Shc/Grb2/Sos and p21ras rather than protein kinase C as reported previously for AngII receptors. These observations provide a novel mechanism for AngII-AT2 receptor-mediated transport modulation.
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PMID:Renal proximal tubular AT2 receptor: signaling and transport. 989 43

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

Little is known of the mechanisms leading to mitogen-activated protein kinase (MAPK) activation via Gq-coupled receptors. We therefore examined the pathways by which angiotensin II (Ang II) activates Raf-1 kinase, an upstream intermediate in the pathway to MAPK, via the Gq-coupled AT1 angiotensin receptor in bovine adrenal glomerulosa (BAG) cells. Ang II caused a rapid and transient activation of Raf-1 that reached a peak at 5-10 min. Ang II was a potent stimulus of Raf-1 activation with an ED50 of 10 pM and a maximal response at 1 nM, although higher Ang II concentrations elicited a submaximal response. Ang II-stimulated Raf-1 activity was unaffected by down-regulation of protein kinase C and intracellular Ca2+ chelation (using BAPTA) but was partially inhibited by pertussis toxin, and was abolished by manumycin A. Removal of extracellular Ca2+ (by EGTA) or blockade of L type Ca2+ channels (by nifedipine), as well as inhibition of MEK-1 kinase (by PD98059), enhanced Raf-1 activity, whereas wortmannin (100 nM) inhibited approximately one half of Ang II-stimulated Raf-1 activity. Hence, Raf-1 kinase activation by Ang II in BAG cells is dependent on Ras, is mediated in part via Gi and phosphatidylinositol 3-kinase, and is negatively regulated via Ca2+ influx and a downstream signaling element(s).
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PMID:Raf-1 kinase activation by angiotensin II in adrenal glomerulosa cells: roles of Gi, phosphatidylinositol 3-kinase, and Ca2+ influx. 1006 66

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

It has been shown that glomerular angiotensin II (ANG II) receptors are downregulated and protein kinase C (PKC) is activated under diabetic conditions. We, therefore, investigated ANG II receptor and PKC isoform regulation in glomerular mesangial cells (MCs) under normal and elevated glucose concentrations. MCs were isolated from collagenase-treated rat glomeruli and cultured in medium containing normal or high glucose concentrations (5.5 and 25.0 mM, respectively). Competitive binding experiments were performed using the ANG II antagonists losartan and PD-123319, and PKC analysis was conducted by Western blotting. Competitive binding studies showed that the AT1 receptor was the only ANG II receptor detected on MCs grown to either subconfluence or confluence under either glucose concentration. AT1 receptor density was significantly downregulated in cells grown to confluence in high-glucose medium. Furthermore, elevated glucose concentration enhanced the presence of all MC PKC isoforms. In addition, PKCbeta, PKCgamma and PKCepsilon were translocated only in cells cultured in elevated glucose concentrations following 1-min stimulation by ANG II, whereas PKCalpha, PKCtheta, and PKClambda were translocated by ANG II only in cells grown in normal glucose. Moreover, no changes in the translocation of PKCdelta, PKCiota, PKCzeta, and PKCmu were detected in response to ANG II stimulation under euglycemic conditions. We conclude that MCs grown in high glucose concentration show altered ANG II receptor regulation as well as PKC isoform translocation compared with cells grown in normal glucose concentration.
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PMID:Regulation of angiotensin II receptors and PKC isoforms by glucose in rat mesangial cells. 1033 51

This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine cardiomyocytes were cultured on malleable silicone dishes and were stretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes. It also caused gel mobility shift of sis-inducing element, which was supershifted by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT1 blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (anti-glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT3 and partially inhibited that of STAT1. Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+/H+ exchanger inhibitor) and BAPTA-AM (intracellular calcium chelator), but not by gadolinium (stretch-activated ion channel inhibitor), EGTA (extracellular Ca2+ chelator), or KN62 (Ca2+/calmodulin kinase II inhibitor). Chelerythrine (protein kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3. Mechanical stretch also augmented the mRNA expression of cardiotrophin-1, interleukin-6, and leukemia inhibitory factor at 60 to 120 minutes. These results indicated that the JAK/STAT pathway was activated by mechanical stretch, and that this activation was partially dependent on autocrine/paracrine-secreted angiotensin II and was mainly dependent on the interleukin-6 family of cytokines but was independent of endothelin-1. Moreover, certain levels of intracellular Ca2+ were necessary for stretch-induced activation of this pathway, and protein kinase C was also partially involved in this activation.
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PMID:Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. 1034 87


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