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)

Changes in adrenal corticosteroid secretion result in changes in lung liquid production in the late-gestation fetus. To test for the presence of mineralocorticoid receptor (MR) in fetal pulmonary epithelium, lungs from fetal sheep of 120 to 130 days' gestation (term about 148 days) were collected and frozen for identification of mRNA for MR in homogenates by reverse transcriptase polymerase chain reaction (RT-PCR) or for determination of 3H-cortisol binding at MR. Other samples of fetal lungs were fixed for localization of MR and Na+, K+ adenosine triphosphatase (ATPase) alpha by immunohistochemistry. MR mRNA was identified in lung tissue from fetuses and newborn lambs, but not from pregnant ewes; MR-regulated genes, including SGK1 and ENaCalpha were also expressed in fetal and newborn lungs. Immunoreactive MR was found in pulmonary epithelial cells and to be colocalized with Na+, K+ ATPase alpha in many sites. These results indicate that the molecular apparatus for mineralocorticoid-stimulated lung liquid reabsorption is present in epithelium by 120 days' gestation.
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PMID:Mineralocorticoid receptor expression in late-gestation ovine fetal lung. 1569 2

Renal transplantation is associated with alterations of tubular functions and of the renin-angiotensin-aldosterone system. The underlying cellular and molecular mechanisms are unclear. We used an allogeneic rat renal transplantation model of acute rejection with and without immunosuppression by cyclosporine A (CsA) and a syngeneic model as control. Uninephrectomized Lewis or Lewis-Brown-Norway (LBN) rats received a kidney from LBN-rats. Renal transporters and receptors were analyzed by immunohistochemistry, semiquantitative RT-PCR and Western-blot analysis. Intracellular Na(+) was analyzed microfluorimetrically in isolated cortical collecting ducts. mRNA expression and function of the epithelial Na(+)-channel (ENaC) and mRNA and protein expression of the water-channel AQP2 were downregulated in transplanted kidneys undergoing rejection. Expression of the serum- and glucocorticoid-kinase (Sgk1) was decreased and that of the ubiquitin-protein ligase Nedd4-2 was increased. These changes were absent under CsA-therapy and in syngeneic model. Expression and function of the Na(+)-K(+)-ATPase, expression of the secretory K(+)-channel and of the mineralocorticoid receptor remained unchanged. Reduced ENaC function is likely due to decreased Sgk1- and increased Nedd4-2 mRNA expression leading to reduced ENaC expression in the membrane. These acute downregulations of ENaC and AQP2 may be triggered to reduce energy consumption in the distal nephron to protect the kidney immediately after transplantation.
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PMID:Acute rejection after rat renal transplantation leads to downregulation of NA+ and water channels in the collecting duct. 1588 31

The water and electrolyte balance is regulated by the renin-angiotensin-aldosterone system in the kidney. We previously reported that the levels of circulating aldosterone dramatically increased following a total proctocolectomy in rats. However, there is no direct evidence regarding whether renal adaptation is accelerated by the induction of aldosterone-associated molecules. To explore this question, Sprague-Dawley rats underwent total proctocolectomies and then were killed 8 weeks later. We investigated the renal expression of 11beta-hydroxysteroid dehydrogenase type 2, the alpha-, beta-, and gamma-subunits of the epithelial sodium channel, and the alpha1- and beta1-subunits of Na+,K+-ATPase mRNAs because those molecules are responsible for the aldosterone specificity for mineralocorticoid receptor, amiloride-sensitive sodium absorption, and sodium extrusion from distal tubules, respectively. A Northern blot analysis demonstrated the kidney to exhibit mRNA induction for all of these molecules, thus supporting the idea that renal adaptation following a total proctocolectomy depends, at least in part, upon the molecular induction which is principally regulated by circulating aldosterone.
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PMID:Renal expression of the essential genes associated with sodium transport following a total proctocolectomy in rats. 1591 2

The lumen of the inner ear has an unusually low concentration of endolymphatic Na+, which is important for transduction processes. We have recently shown that glucocorticoid receptors (GR) stimulate absorption of Na+ by semicircular canal duct (SCCD) epithelia. In the present study, we sought to determine the presence of genes involved in the control of the amiloride-sensitive Na+ transport pathway in rat SCCD epithelia and whether their level of expression was regulated by glucocorticoids using quantitative real-time RT-PCR. Transcripts were present for alpha-, beta-, and gamma-subunits of the epithelial sodium channel (ENaC); the alpha1-, alpha3-, beta1-, and beta3-isoforms of Na+-K+-ATPase; inwardly rectifying potassium channels [IC50 of short circuit current (Isc) for Ba2+: 210 microM] Kir2.1, Kir2.2, Kir2.3, Kir2.4, Kir3.1, Kir3.3, Kir4.1, Kir4.2, Kir5.1, and Kir7.1; sulfonyl urea receptor 1 (SUR1); GR; mineralocorticoid receptor (MR); 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2; serum- and glucocorticoid-regulated kinase 1 (Sgk1); and neural precursor cell-expressed developmentally downregulated 4-2 (Nedd4-2). On the other hand, transcripts for the alpha4-subunit of Na+-K+-ATPase, Kir1.1, Kir3.2, Kir3.4, Kir6.1, Kir6.2, and SUR2 were found to be absent, and Isc was not inhibited by glibenclamide. Dexamethasone (100 nM for 24 h) not only upregulated the transcript expression of alpha-ENaC (approximately 4-fold), beta2-subunit (approximately 2-fold) and beta3-subunit (approximately 8-fold) of Na+-K+-ATPase, Kir2.1 (approximately 5-fold), Kir2.2 (approximately 9-fold), Kir2.4 (approximately 3-fold), Kir3.1 (approximately 3- fold), Kir3.3 (approximately 2-fold), Kir4.2 (approximately 3-fold), Kir7.1 (approximately 2-fold), Sgk1 (approximately 4-fold), and Nedd4-2 (approximately 2-fold) but also downregulated GR (approximately 3-fold) and 11beta-HSD1 (approximately 2-fold). Expression of GR and 11beta-HSD1 was higher than MR and 11beta-HSD2 in the absence of dexamethasone. Dexamethasone altered transcript expression levels (alpha-ENaC and Sgk1) by activation of GR but not MR. Proteins were present for the alpha-, beta-, and gamma-subunits of ENaC and Sgk1, and expression of alpha- and gamma-ENaC was upregulated by dexamethasone. These findings are consistent with the genomic stimulation by glucocorticoids of Na+ absorption by SCCD and provide an understanding of the therapeutic action of glucocorticoids in the treatment of Meniere's disease.
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PMID:Glucocorticoid regulation of genes in the amiloride-sensitive sodium transport pathway by semicircular canal duct epithelium of neonatal rat. 1626 2

Aldosterone may play a pivotal role in the pathophysiology of heart failure. To elucidate the beneficial cardioprotective mechanism of eplerenone, a novel selective aldosterone blocker, we hypothesized that eplerenone stimulates endothelial NO synthase (eNOS) through Akt and inhibits inducible NO synthase (iNOS) via nuclear factor kappaB (NF-kappaB) after the development of oxidative stress and activation of the lectin-like, oxidized, low-density lipoprotein receptor 1 (LOX-1) pathway in Dahl salt-sensitive rats with heart failure. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of the left ventricular hypertrophy stage (11 weeks) to the failing stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship was evaluated using a conductance catheter. Decreased percentage of fractional shortening by echocardiography and end-systolic pressure-volume relationship in failing rats was significantly ameliorated by eplerenone. Downregulated eNOS expression, eNOS and Akt phosphorylation, and NOS activity in failing rats were increased by eplerenone. Upregulated expression of the mineralocorticoid receptor aldosterone synthase (CYP11B2); NAD(P)H oxidase p22phox, p47phox, gp91phox, iNOS, and LOX-1; and activated p65 NF-kappaB, protein kinase CbetaII, c-Src, p44/p42 extracellular signal-regulated kinase, and p70S6 kinase phosphorylation were inhibited by eplerenone. Eplerenone administration resulted in significant improvement of cardiac function and remodeling and upregulation of sarcoplasmic reticulum Ca(2+)-ATPase expression. These findings suggest that eplerenone may have significant therapeutic potential for heart failure, and these cardioprotective mechanisms of eplerenone may be mediated in part by stimulating eNOS through Akt and inhibiting iNOS via NF-kappaB after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway.
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PMID:Cardioprotective mechanisms of eplerenone on cardiac performance and remodeling in failing rat hearts. 1650 12

The steroid hormone aldosterone is a major regulator of extracellular volume and blood pressure. Aldosterone effectors are for example the epithelial Na(+) channel (ENaC), the Na(+)-K(+)-ATPase and the proximal tubule Na(+)/H(+) exchanger isoform 3 (NHE3). The aim of this study was to investigate whether aldosterone acts directly on proximal tubule cells to stimulate NHE3 and if so whether the EGF-receptor (EGFR) is involved. For this purpose, primary human renal proximal tubule cells were exposed to aldosterone. NHE3 activity was determined from Na(+)- dependent pH-recovery, NHE3 surface expression was determined by biotinylation and immunoblotting. EGFR-expression was assessed by ELISA. pH(i)- measurements revealed an aldosterone-induced increase in NHE3 activity, which was inhibited by the mineralocorticoid receptor blocker spironolactone and by the EGFR-kinase inhibitor AG1478. Immunoprecipitation and immunoblot analysis showed an aldosterone-induced increase in NHE3 surface expression, which was also inhibited by spironolactone and AG1478. Furthermore, aldosterone enhanced EGFR-expression. In conclusion, aldosterone stimulates NHE3 in human proximal tubule cells. The underlying mechanisms include AG1478 inhibitable kinase and are paralleled by enhanced EGFR expression, which could be compatible with EGF-receptor-pathway-dependent surface expression and activity of NHE3 in human primary renal proximal tubule epithelial cells.
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PMID:Aldosterone stimulates activity and surface expression of NHE3 in human primary proximal tubule epithelial cells (RPTEC). 1654 18

Aldosterone induces redistribution of epithelial sodium channel (ENaC) to the apical plasma membrane from intracellular vesicles in renal connecting tubule (CNT) and cortical collecting duct (CCD). The role of the classical mineralocorticoid receptor (MR) in ENaC trafficking is still debated. We examined whether the MR antagonist spironolactone affects ENaC regulation in the kidney cortex of aldosterone-infused rats. Aldosterone infusion for 7 days resulted in a plasma aldosterone concentration in the high physiological range (3 to 4 nM). Aldosterone infusion decreased plasma K(+) concentration compared with untreated control rats. Cotreatment with spironolactone completely blocked the aldosterone-induced decrease in plasma K(+). Immunoblotting and immunohistochemistry showed increased protein abundance of Na-K-ATPase alpha(1)-subunit and NCC in the kidney cortex, in response to aldosterone infusion that was blocked by spironolactone. In contrast, aldosterone-induced redistribution of ENaC subunits from the cytoplasm to the apical plasma membrane domain in CNT and CCD was unaffected by spironolactone. Immunoblotting of alphaENaC showed increased protein abundance in aldosterone-infused rats that was not blocked by spironolactone treatment. To exclude possible glucocorticoid receptor (GR)-mediated effects of aldosterone, we treated aldosterone-infused rats with both spironolactone and the GR antagonist RU486. Combined MR and GR blockade prevented neither ENaC trafficking nor the upregulation of alphaENaC protein abundance in aldosterone-infused rats. We provide new evidence for ENaC trafficking occurring independent of MR and GR activation in aldosterone-infused rats.
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PMID:Maintained ENaC trafficking in aldosterone-infused rats during mineralocorticoid and glucocorticoid receptor blockade. 1691 64

This is the first study to report concurrent dynamics in mRNA expression of growth hormone receptor (GHR), prolactin receptor (PRLR), gluco- and mineralocorticoid receptor (GR and MR) and the 11beta-hydroxysteroid dehydrogenase type-2 enzyme (11beta-HSD2) in Atlantic salmon (Salmo salar) gill during smoltification. Transcript levels were analysed by quantitative PCR in fresh water (FW) fish and after a 24-h salt water (SW) challenge. GHR transcript levels increased concurrent with gill Na(+),K(+)-ATPase activity in FW fish consistent with the SW-adaptive role of GH. SW-transfer induced an increased GHR expression levels in the early stages of smoltification but a decrease in expression at the peak of smoltification. PRLR transcript levels decreased steadily during smoltification in agreement with the recognized hyper-osmoregulatory role of PRL. Surprisingly, PRLR levels increased after SW transfer during the course of smoltification. GR mRNA levels were low early on during smoltification but increased at the peak of smoltification and remained high during de-smoltification, indicative of increased cortisol signalling at this point. Coherently, SW transfer increased GR levels to smolt levels prior to the smoltification peak. 11beta-HSD2 levels increased at the smoltification peak and MR levels increased during de-smoltification, suggesting a need for protection of MR from cortisol signalling during smoltification. This is supported by the fact that SW-transfer results in a profound up-regulation of 11beta-HSD2, whereas SW transfer down-regulates MR levels. The study concludes that GR and MR may have distinctive roles in developing hypo- and hyper-osmoregulatory mechanisms during smoltification and de-smoltification, respectively.
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PMID:Hormone receptors in gills of smolting Atlantic salmon, Salmo salar: expression of growth hormone, prolactin, mineralocorticoid and glucocorticoid receptors and 11beta-hydroxysteroid dehydrogenase type 2. 1728 45

Marinobufagenin (MBG) is a cardiotonic steroid of the bufadienolide class of compounds which has the ability to inhibit the ubiquitous enzyme, Na+/K+-ATPase, resulting in natriuresis. The involvement of MBG in the pathogenesis of volume expansion-mediated forms of hypertension has been suggested for some time, and we have proposed that MBG participates in the hypertension noted in preeclampsia. We examined the hypothesis that MBG might contribute to these forms of hypertension by promoting the activity of the mineralocorticoid receptor (MR). However, our data demonstrate that instead, MBG interferes with the functioning of the MR by inhibiting the transcriptional activity of the receptor, and this is reflected in a reduced interaction between the SRC-3 coactivator and the MR. Thus, the ability of MBG to cause a natriuresis may be due, not only to inhibition of Na+/K+-ATPase activity, but also to its ability to interfere with MR-dependent expression of the Na/K/H exchanger in the late distal nephron.
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PMID:Marinobufagenin interferes with the function of the mineralocorticoid receptor. 1739 82

Fetal glucocorticoid excess leads to subsequent adult hypertension, but the mechanisms involved in this developmental programming remain largely unknown. In this study we tested the hypothesis that programmed hypertension in rats is linked to altered renal expression of the glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase type 2 and components of the intrarenal and adipose renin-angiotensin system. The interactive effects of a postnatal diet enriched in omega-3 fatty acids, which prevents emergence of the hypertensive phenotype, were also examined. Maternal dexamethasone (0.75 microg/mL of drinking water from day 13 to term) markedly increased renal expression of the glucocorticoid receptor in 6-month-old offspring, and this was associated with hypomethylation of the glucocorticoid receptor promoter; renal MR was unaffected. In contrast, maternal dexamethasone reduced renal 11beta-hydroxysteroid dehydrogenase type 2 in offspring, but this effect was prevented by a high omega-3 diet. Consistent with these effects, renal Na/K-ATPase-alpha1 was elevated in offspring of dexamethasone-treated mothers, but only in those raised on the standard diet. Maternal dexamethasone also programmed increased expression of renal and adipose angiotensin-converting enzyme and renal renin, but among these changes, only that of renal angiotensin-converting enzyme was prevented by the omega-3 diet. Our data support the hypothesis that programmed hypertension is mediated, in part, by increased renal glucocorticoid sensitivity, with consequent stimulatory effects on Na/K-ATPase-alpha1 and intrarenal renin-angiotensin system components. Partial prevention of programmed changes in renal gene expression by postnatal dietary omega-3 fatty acids provides insight into how this intervention prevents hypertension induced by fetal glucocorticoid excess.
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PMID:Developmental programming of renal glucocorticoid sensitivity and the renin-angiotensin system. 1766 94


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