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: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aldosterone, like other steroid hormones, initiates its effects by binding to intracellular receptors; these receptors are then able to control the transcription of several genes. The products of these genes eventually modulate the activity of ionic transport systems located in the apical and the basolateral membrane of specialized epithelial cells, thereby modulating the excretion of Na+ and K+ ions. Considerable progress has been made recently in understanding these mechanisms and the structure of the proteins involved in these processes. A novel principle has been discovered to explain the selective effect of aldosterone on its target epithelia. These tissues exclude competing glucocorticoid hormones by the activity of the 11 beta-hydroxysteroid dehydrogenase to allow aldosterone, an enzyme-resistant steroid, to bind to its receptors. Aldosterone induces numerous changes in the activity of membrane ion transport systems and enzymes and cell morphology. Although the enhancement of Na,K-ATPase synthesis and the increase of the number of active Na+ channels in the apical membrane appear as both direct and primary effects, the mechanisms of the other effects remain to be determined. The knowledge of the primary structure of several elements of the aldosterone response system (e.g., mineralocorticoid receptor and Na,K-ATPase) allows us to understand abnormal regulation of Na+ balance at the molecular level and, potentially, to identify genetic alterations responsible for these defects.
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PMID:Aldosterone regulation of gene transcription leading to control of ion transport. 137 88

We have previously demonstrated that baroreceptor discharge sensitivity is depressed in dogs with experimental heart failure and that this depressed sensitivity can be reversed by the Na+,K(+)-ATPase inhibitor ouabain. This suggests that enhanced Na+,K(+)-ATPase activity in baroreceptors is responsible for the blunted baroreceptor discharge sensitivity seen in heart failure state. Because aldosterone, a known stimulator of Na+,K(+)-ATPase, is elevated in heart failure the present study was undertaken to determine the effects on baroreceptor discharge of perfusion of the carotid sinus with aldosterone in normotensive dogs. Single unit baroreceptor activity was recorded as well as carotid sinus pressure and the diameter of the carotid sinus. Perfusion of the carotid sinus with aldosterone (in Krebs-Henseleit solution) significantly elevated threshold pressure (108.5 +/- 3.1 mm Hg versus 92.7 +/- 4.6 mm Hg, p less than 0.05) and reduced peak discharge rate (40.3 +/- 3.9 spikes/sec, p less than 0.05). These effects appeared 15 minutes after aldosterone perfusion and remained constant for the next 60 minutes. There was no change in the carotid sinus pressure-diameter curve during perfusion with aldosterone. Perfusion of the carotid sinus with ouabain (0.1 microgram/ml) during aldosterone perfusion did not reverse the blunted baroreceptor discharge. The blunted baroreceptor activity induced by perfusion of the carotid sinus with aldosterone was prevented by removal of the endothelial cells in the carotid sinus area with a balloon-tipped catheter or by perfusion with saponin. Finally, perfusion of the carotid sinus with spironolactone (10 ng/ml), a mineralocorticoid receptor antagonist, prevented the inhibitory effect of aldosterone. These data suggest that aldosterone reduces maximum baroreceptor discharge.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aldosterone reduces baroreceptor discharge in the dog. 154 52

To investigate the direct epithelial effects of corticosteroids on renal ion transport, we studied the influence of the pure glucocorticoid agonist RU 28362 and aldosterone on Na+ and K+ transport in primary cultures of immunodissected rabbit cortical collecting duct (CCD) cells. When grown on permeable supports in a steroid-free medium, CCD monolayers exhibited a lumen-negative transepithelial potential difference (PD) of 5.2 +/- 1.07 mV and a short-circuit current (SCC) of 8.54 +/- 2.2 microA/cm2. Transepithelial resistance averaged 660 +/- 49 omega/cm2. The cultures actively reabsorbed Na+ and secreted K+. Both aldosterone and RU 28362 significantly increased PD and SCC; the effects were time and dose dependent. The effect of RU 28362 was completely prevented by the glucocorticoid receptor antagonist RU 486, whereas ZK 91587, a specific mineralocorticoid receptor antagonist, did not block its effect. Both aldosterone and RU 28362 increased the bath-to-lumen concentration ratio of Na+ while lowering that of K+, indicating an increased Na+ reabsorption and K+ secretion. The number of Na(+)-K(+)-ATPase units was significantly enhanced (approximately 2-fold) by both RU 28362 and aldosterone. These results demonstrate that, in cultured CCD cells, not only aldosterone but also a pure glucocorticoid is able to exert mineralocorticoid-like effects, and this latter effect is mediated by glucocorticoid receptors. Because all parameters studied responded similarly to aldosterone and RU 28362, we speculate that in CCD cells glucocorticoids and mineralocorticoids might act by regulating the same gene(s).
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PMID:Glucocorticoid receptors mediate mineralocorticoid-like effects in cultured collecting duct cells. 222 Nov 5

Several epithelial ion transporters are developmentally regulated in the preweaning period, at the time when the circulating levels of glucocorticoid and mineralocorticoid hormones increase. The specific role of glucocorticoids and mineralocorticoids in the maturation of epithelial ion transport is still disputed. In this study, we investigated the effect of corticosteroids on the mRNA expression of ion transporters in the infant rat colon, a glucocorticoid- and mineralocorticoid-sensitive organ. The expression of the Na,K-ATPase, the H,K-ATPase and the amiloride-sensitive Na+ channel mRNA was investigated in control rats from fetal to adult life. We found that the mRNA of the three transporters is temporarily up-regulated in the preweaning period. Rats were then injected with a single dose of betamethasone or aldosterone at 10 d of age. The main effect was the glucocorticoid stimulation of the Na,K-ATPase mRNA within 6 h (4-fold). Glucocorticoids did not alter H,K-ATPase nor Na+ channel mRNA within 6 h. Aldosterone moderately (1.7-fold) stimulated Na+ channel within 6 h, but dit not alter Na,K-ATPase nor H,K-ATPase mRNA. Twenty-four hours after injection, both glucocorticoids and mineralocorticoids had less pronounced and distinct effects. In tissue with lower aldosterone receptor abundance (renal cortex) or with no aldosterone receptor (stomach), glucocorticoids induce a similarly rapid increases in Na,K-ATPase mRNA (4-fold within 6 h), whereas aldosterone had no effect within 6 h. However, glucocorticoids did not stimulate Na,K-ATPase mRNA in the brain, a tissue rich in glucocorticoid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effects of glucocorticoids and mineralocorticoids on the mRNA expression of colon ion transporters in infant rats. 747 10

To examine a physiological role of 11 beta-hydroxysteroid dehydrogenase (11OHSD) in the aldosterone target tissue, we measured Na(+)-K(+)-ATPase activity in the cortical collecting ducts (CCD) from adrenalectomized rats, which were treated with a physiological dose of corticosterone and/or carbenoxolone (an inhibitor of 11OHSD). The Na(+)-K(+)-ATPase activity in adrenalectomized rats was not significantly changed by either corticosterone alone or carbenoxolone alone, whereas its activity showed a significant increase only in the rats that received both corticosterone and carbenoxolone. In these rats, the plasma concentration of corticosterone was within the physiological range (10(-6) M) and the plasma carbenoxolone concentration was about 10(-7) M. Furthermore, the direct effect of carbenoxolone was examined in the microdissected CCD because it has been reported that carbenoxolone per se had an affinity for the aldosterone receptor. Na+K(+)-ATPase activity in the microdissected CCD was increased in a dose-dependent manner after a 3-hour incubation with carbenoxolone, and this effect was completely inhibited by canrenoic acid (an aldosterone antagonist). However, the minimal carbenoxolone concentration exerting a stimulatory effect was 10(-6) M, which is about 10 times higher than the plasma concentration of carbenoxolone in the in vivo treated rats. These results indicate that an inhibition of 11OHSD but not a direct action of carbenoxolone induces an increase in Na(+)-K(+)-ATPase activity, which is a well-known aldosterone effect in the CCD.
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PMID:Corticosterone increases Na(+)-K(+)-ATPase activity in rat cortical collecting ducts with inhibition of 11 beta-hydroxysteroid dehydrogenase. 753 35

Mineralocorticoid hormones such as aldosterone modulate cellular ion homeostasis at least in part through the regulation of Na+, K(+)-ATPase (NAKA) gene expression. While aldosterone acts at the transcriptional level through its ligand-inducible mineralocorticoid receptor (MR), tissue specific and other transcriptional factors may interact with the MR to modulate this regulatory response. cAMP also regulates NAKA alpha 1 gene expression which at the transcriptional level is mediated, in part, through a cAMP response element (CRE) present on a highly conserved, 48 base pair enhancer region, the PUC-1 core, of the rat NAKA alpha 1 subunit gene promoter. We have tested the hypothesis that the MR interacts with cAMP induced transcriptional factors to modulate the NAKA alpha 1 gene expression. In transient transfection studies a PUC-1 core attached to an enhancerless SV40 promoter driven reporter gene (pB1CAT) was induced by 8-bromo-cAMP in HeLa cells. Co-transfected MR expression vector inhibited the 8-bromo-cAMP inducible activity of pB1CAT. DNA binding studies suggested that the PUC-1 core binds both CREB/ATF proteins as well as the glucocorticoid hormone class of steroid receptors. These results suggest that the MR suppresses cAMP-mediated activation of PUC-1 core driven CAT activity possibly through a direct interaction with CREB/ATF transcriptional factors. This in turn suggests that the interaction of two distinct signal transduction systems, aldosterone and cAMP, may define the mineralocorticoid responsiveness of the Na+, K(+)-ATPase alpha 1 gene.
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PMID:Evidence for the regulation of Na+, K(+)-ATPase alpha 1 gene expression through the interaction of aldosterone and cAMP-inducible transcriptional factors. 779 1

The induction of Na,K-ATPase plays a vital role in mediating epithelial sodium transport. Although its activity is regulated by corticosteroids, it is uncertain whether this is predominantly by mineralo- or glucocorticoid mechanisms. 11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the interconversion of active corticosterone (B) to inactive 11-dehydrocorticosterone and protects the nonselective mineralocorticoid receptor (MR) from glucocorticoid excess. We have studied the regulation of the alpha 1- and beta 1-subunits of Na,K-ATPase by mineralo- and glucocorticoids in vitro and in vivo, and how this is modulated by 11 beta HSD activity. Cultured rat kidney epithelial cells (NRK 52-E) expressed 11 beta HSD activity, which was inhibited by the licorice derivative glycyrrhetinic acid (GE). Dexamethasone, aldosterone, and high concentrations of B (1-10 microM) increased Na,K-ATPase alpha 1 and beta 1 messenger RNA (mRNA) levels, an effect that was inhibited by coincubation with the MR antagonist RU 26752, but not by the glucocorticoid receptor antagonist RU 38486. GE, which itself reduced Na,K-ATPase alpha 1/beta 1 mRNA levels, potentiated the action of B, so that low concentrations of B (10 nM) increased Na,K-ATPase alpha 1/beta 1 mRNA levels. In contrast, in vivo, RU 26752 and RU 38486 given ip for 4 days (n = 6/group) reduced renal Na,K-ATPase alpha 1 and beta 1 levels. Glycyrrhizic acid also inhibited both renal 11 beta HSD mRNA and activity and levels of Na,K-ATPase alpha 1/beta 1 mRNA. In vivo renal Na,K-ATPase subunit mRNA levels are regulated by both mineralo- and glucocorticoid mechanisms. In vitro, however, although NRK 52-E cells expressed the glucocorticoid receptor, corticosteroid regulation of Na,K-ATPase, even by dexamethasone, occurred exclusively via the MR, suggesting that accessory transcription factors required for glucocorticoid hormone action are absent in this cell line. Finally, although the licorice derivatives GE and glycyrrhizic acid reduced Na,K-ATPase alpha 1/beta 1 mRNA levels, they also potentiated the stimulatory effect of B by inhibiting its metabolism via 11 beta HSD, establishing 11 beta HSD as an important prereceptor modulator of mineralocorticoid hormone action.
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PMID:Regulation of sodium-potassium adenosine triphosphate subunit gene expression by corticosteroids and 11 beta-hydroxysteroid dehydrogenase activity. 807 Mar 85

In normal physiology 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) protects the mineralocorticoid receptor (MR) from glucocorticoid excess. In the rat, however, 11 beta-OHSD mRNA and activity is widespread, suggesting that it may also play a role in regulating ligand access to the glucocorticoid receptor (GR). We have studied the role of the 11 beta-OHSD in modulating corticosteroid hormone action in rat pituitary GH3 cells (glucocorticoids inhibit prolactin gene transcription) and renal epithelial NRK-52E cells (mineralocorticoids increase Na-K ATPase subunit gene expression) in culture. Both cell lines express high levels of 11 beta-OHSD activity, and Northern/Western blot analyses using a rat cDNA probe and antisera raised against rat liver 11 beta-OHSD reveal a single 1.4 Kb mRNA encoding an enzyme of molecular size 34 kDa. In GH3 cells, prolactin gene transcription was unaffected by corticosterone (B) in doses of 10(-8) to 10(-6) M. When 11 beta-OHSD activity was inhibited with the licorice derivative, glycyrrhetinic acid (GE); however, 10(-6) M B inhibited prolactin (PRL) mRNA levels to the same degree as an equimolar concentration of the GR agonist RU 28362. This effect was blocked by co-incubation with the GR antagonist RU 38486. In NRK-52E cells, co-incubation with B and GE resulted in a marked increase in alpha 1/beta 1 Na-K ATPase subunit mRNA levels when compared with GE and/or B alone and this effect could be blocked by administration of the MR antagonist RU 26752.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:11 beta-Hydroxysteroid dehydrogenase activity and corticosteroid hormone action. 819 54

To determine whether gluco- and mineralocorticoids have specific actions on Na+-K+-ATPase gene expression in vascular tissue, we used Northern blot analysis to compare the effects of dexamethasone (Dex) and aldosterone (Aldo) on Na+-K+-ATPase alpha1 and beta1-subunit mRNA expression in cultured vascular smooth muscle cells from rat aortae. Dex at 10(-6)M increased alpha1 -mRNA level 2.5-fold at 24 h and beta1-mRNA level 9.9-fold at 12 h. Aldo at 10(-6)M increased alpha1-mRNA 2.7-fold at 48 h and beta1-mRNA level 10.9-fold at 6 h. The half-maximal stimulation of both alpha1 and beta1-mRNA levels occurred at a concentration of 5-7 X 10(-9)M Dex, whereas it occurred at a concentration of 2-3 X 10(-9)M Aldo. The glucocorticoid receptor antagonist RU-38486 inhibited both Dex- and Aldo-mediated induction of beta1-mRNA. The mineralocorticoid receptor antagonist spironolactone inhibited Aldo-mediated induction of beta1-mRNA, whereas it had no effect on Dex-mediated induction of beta1-mRNA. Removal of Na+ from the extracellular medium (isosmotic replacement with choline) caused no effect on Dex-mediated induction beta1-mRNA, whereas it inhibited Aldo-mediated induction of beta1-mRNA. Addition of a specific inhibitor of the Na+/H+ exchange, ethylisopropylamiloride, had no effect on Dex-mediated induction of beta1-mRNA, whereas it resulted in a significant inhibition of Aldo-mediated induction of beta1-mRNA. We conclude that 1) both Dex and Aldo induce Na+-K+-ATPase alpha1- and beta1-mRNA expression in a time- and dose-dependent manner; 2) Dex-mediated induction of beta1-mRNA occurs only through glucocorticoid receptors, whereas Aldo-mediated induction of beta1-mRNA occurs through both gluco- and mineralocorticoid receptors; and 3) Dex-mediated induction of beta1-mRNA occurs through Na+-independent mechanisms, whereas Aldo-mediated induction of beta1-mRNA, at least in part, occurs through Na+-dependent mechanisms, including stimulation of the Na+/H+ exchange.
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PMID:Differential regulation of Na+-K+-ATPase gene expression by corticosteriods in vascular smooth muscle cells. 863 51

We have previously reported that the Wistar/Furth (W/Fu) rat strain is resistant to mineralocorticoid hypertension. In the current study, we have examined renal mRNA levels for mineralocorticoid receptor (MR), glucocorticoid receptor (GR), renin and Na+, K(+)-ATPase in response to treatment with mineralocorticoids. Uninephrectomized male Wistar (WI) and W/Fu rats were treated with aldosterone or deoxycorticosterone acetate (DOCA) and were given 1% NaCl to drink. Rats were sacrificed after 1, 3 or 7 days of treatment. Renal MR and ATPase mRNA levels were significantly reduced in aldosterone and DOCA-treated WI rats (e.g. MR was 30% on day 3 and ATPase was 50% of control on day 7 of aldosterone treatment). Unexpectedly, GR mRNA levels paralleled the changes in MR. In W/Fu rats the level of message was either unchanged or only moderately altered by this treatment. In vivo administration of the MR antagonist RU28318 or the GR antagonist RU38486 to WI rats for 4 days reduced renal mRNA levels for both subunits of ATPase. In the W/Fu rat, this treatment resulted in no change in the alpha subunit and an increase in the beta subunit of ATPase. In preliminary studies, we have determined that the W/Fu rat is also resistant to dexamethasone-induced hypertension. These studies suggest that altered MR- and GR-mediated mechanisms may contribute to the resistance of the W/Fu rat strain to steroid-induced hypertension.
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PMID:The resistance of the Wistar/Furth rat strain to steroid hypertension. 896 28


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