Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Keratinocyte growth factor (KGF) caused cystic dilation of mouse fetal lung explants in vitro, markedly increasing the luminal volume of lung buds and disrupting branching morphogenesis. Effects of KGF were dose dependent, were detected within 4 h of treatment, and were blocked by cycloheximide but not by actinomycin D, indicating that de novo protein synthesis mediated the response. Effects of KGF were inhibited by bumetanide, an inhibitor of the Na(+)-K(+)-Cl- cotransporter, and ouabain, an inhibitor of the Na(+)-K(+)-ATPase. KGF stimulated fluid secretion equally in lung buds from cystic fibrosis transmembrane conductance regulators (CFTR) -/- and wild-type embryos, indicating that the effects were mediated by CFTR-independent Cl- transport. Microelectrode studies demonstrated that, whereas KGF did not acutely alter the transepithelial potential difference (PD) across the respiratory epithelium, the PD decreased while luminal volume increased during chronic exposure. KGF inhibited expression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) mRNA, suggesting that KGF may inhibit Na+ absorption, which may contribute to KGF-induced fluid accumulation. KGF-induced fluid accumulation is driven by CFTR-independent Cl- transport and associated with decreased expression of alpha-ENaC.
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PMID:Keratinocyte growth factor stimulates CFTR-independent fluid secretion in the fetal lung in vitro. 899 70

1. At birth, rapid removal of lung liquid from potential airspaces is required to establish pulmonary gas exchange. To investigate the role for water channels, aquaporins (AQP) and ion transporters in this process, the mRNA expression of AQP, Na+,K(+)-ATPase and the amiloride-sensitive Na+ channel (ENaC) were studied in the fetal and postnatal rat lung. 2. The mRNA expression of all transporters studied increased postnatally. 3. The following water channels were expressed in the lung, AQP1, 4 and 5. The most specific perinatal induction pattern was observed for AQP4. A sharp and transient increase of AQP4 mRNA occurred just after birth coinciding with the time course for clearance of lung liquid. This transient induction of AQP4 mRNA at birth was lung-tissue specific. Around birth there was a moderate increase in AQP1 mRNA, which was not transient. AQP5 increased continuously until adulthood. 4. Fetal lung AQP4 mRNA was induced by both beta-adrenergic agonists and glucocorticoid hormone, which are factors that have been suggested to accelerate the clearance of lung liquid. 5. Immunocytochemistry revealed that AQP4 was located in the basolateral membranes of bronchial epithelia in newborn rats, consistent with the view that this is the major site for perinatal lung liquid absorption. 6. The Na+,K(+)-ATPase alpha 1 subunit and ENaC alpha-subunit mRNA also increased around birth, suggesting that they co-operatively facilitate lung liquid clearance at birth. 7. These data indicate that removal of lung liquid at birth is associated with pronounced and well-synchronized changes in the expression of AQP and the ion transporters studied. The transient perinatal induction of AQP4, which could be prenatally induced by beta-adrenergic agonists, and the localization of this water channel strongly suggest that it plays a critical role for removal of lung liquid at the time of birth.
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PMID:Perinatal changes in expression of aquaporin-4 and other water and ion transporters in rat lung. 940 67

The mineralocorticoid hormone aldosterone stimulates transcellular Na+ reabsorption across target epithelia after a lag period of 20 to 60 min by first activating preexisting channels (epithelial sodium channels, ENaC) and pumps (Na-K-ATPase) and, subsequently, increasing the overall transport capacity of the cells. Both these early regulatory and late anabolic-type actions depend on the transcriptional regulation exerted by hormone-activated mineralocorticoid and/or glucocorticoid receptors (MR and/or GR). Starting at the transcriptional side of the aldosterone action, recent studies have identified the small G protein K-Ras2 and the kinase sgk as the first early aldosterone-induced gene products potentially regulating Na+ transport. At the level of the Na+ transport effectors, much knowledge about ENaC and Na-K-ATPase structure-function relationship and regulation has accumulated. However, the regulatory pathway(s) that link the transcriptional action of aldosterone to these Na+ transport proteins is still to a large extent unknown. The available data suggest that the early regulatory action of aldosterone is pleiotropic, similarly to the late anabolic-type action. The early Na+ transport stimulation would be mediated by the rapid induction of gene products belonging to the regulatory network that integrates the inputs of diverse pathways and finally controls the function of the Na+ transport machinery.
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PMID:Early aldosterone action: toward filling the gap between transcription and transport. 1048 14

Teleost fishes, living in fresh water, engage in active ion uptake to maintain ion homeostasis. Current models for NaCl uptake involve Na(+) uptake via an apical amiloride-sensitive epithelial Na(+) channel (ENaC), energized by an apical vacuolar-type proton pump (V-ATPase) or alternatively by an amiloride-sensitive Na(+)/H(+) exchange (NHE) protein, and apical Cl(-) uptake mediated by an electroneutral, SITS-sensitive Cl(-)/HCO(3-) anion-exchange protein. Using non-homologous antibodies, we have determined the cellular distributions of these ion-transport proteins to test the predicted models. Na(+)/K(+)-ATPase was used as a cellular marker for differentiating branchial epithelium mitochondria-rich (MR) cells from pavement cells. In both the freshwater tilapia (Oreochromis mossambicus) and rainbow trout (Oncorhynchus mykiss), V-ATPase and ENaC-like immunoreactivity co-localized to pavement cells, although apical labelling was also found in MR cells in the trout. In the freshwater tilapia, apical anion-exchanger-like immunoreactivity is found in the MR cells. Thus, a freshwater-type MR chloride cell exists in teleost fishes. The NHE-like immunoreactivity is associated with the accessory cell type and with a small population of pavement cells in tilapia.
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PMID:NaCl uptake by the branchial epithelium in freshwater teleost fish: an immunological approach to ion-transport protein localization. 1088 67

We investigated the regulation of sodium absorption by steroid hormones in embryologically diverse cells from the human eye. A cell extract from human corneal fibroblasts was positive for both the epithelial sodium channel (ENaC) and the mineralocorticoid receptor (MCR) as 82- to 85-kD and 102-kD bands, respectively, by the Western blot technique. In fluorescent, confocal and electron microscopy, the MCR was revealed as a nucleocytoplasmic protein, whereas the ENaC was almost exclusively membrane bound; both appeared aligned along actin filaments of corneal keratocytes, and both were widely colocalized in various cell types of human cornea in situ. Following reverse transcription and amplification of total RNA isolated from corneal fibroblasts, the ENaC and MCR genes in the PCR product were evident as predicted bands of 520 and 843 bp, respectively, whose sequence exhibited 100% identity with those from known human sources. The multiplication of corneal fibroblasts was influenced by both the MCR-specific antagonist RU 26752 and the natural hormone aldosterone, and these steroids also stimulated protein phosphorylation. In quantitative PCR, both the basal and aldosterone-induced levels of ENaC were diminished by the MCR-specific antagonist ZK 91587. Consequently, the ocular sodium channel appears to be regulated by steroid signalling in cells of diverse embryological origins, contrary to the existing notions where (a) this process would be limited exclusively to the epithelial cells and (b) ocular sodium transport would be regulated via the Na(+)-K(+)-ATPase in the basolateral membrane.
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PMID:Mineralocorticoid hormone signaling regulates the 'epithelial sodium channel' in fibroblasts from human cornea. 1111 99

Lung epithelial ion transport promotes salt and water movement across the fetal and neonatal lung epithelium. The mechanism is dependent on basolateral membrane Na-K-ATPase and the apical membrane Cl(-) and Na(+) channels. During fetal life active secretion of Cl(-) and parallel movement of Na(+) across the epithelium into the developing lung lumen induce accumulation of liquid into the future airspaces. Postnatally, however, absorption of fluid from the airspaces must start. Present evidence suggests that activation of Na(+) transport from the lumen into the basolateral direction drives fluid absorption and results in an essentially dry air-filled alveolus. In laboratory animals amiloride, a Na(+) channel blocker, induces respiratory distress and impedes lung fluid clearance. One of the epithelial amiloride-sensitive Na(+) channels, ENaC, is composed of three homologous subunits that differentially respond to glucocorticoid hormone. In newborn infants an increase in pulmonary fluid and a defective Na(+) transport associate with respiratory distress. The ontogeny, subunit composition and function of ENaC along the respiratory tract are currently under investigation. It will be interesting to find out whether the subunit composition and function of lung ENaC respond to the therapy of the critically ill newborn infant.
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PMID:Lung epithelial ion transport in neonatal lung disease. 1135 39

Renal sodium retention, as a result of increased abundance of sodium transporters, may play a role in the development and/or maintenance of the increased blood pressure in obesity. To address this hypothesis, we evaluated the relative abundances of renal sodium transporters in lean and obese Zucker rats at 2 and 4 mo of age by semiquantitative immunoblotting. Mean systolic blood pressure was higher in obese rats relative to lean at 3 mo, P < 0.02. Furthermore, circulating insulin levels were 6- or 13-fold higher in obese rats compared with lean at 2 or 4 mo of age, respectively. The abundances of the alpha(1)-subunit of Na-K-ATPase, the thiazide-sensitive Na-Cl cotransporter (NCC or TSC), and the beta-subunit of the epithelial sodium channel (ENaC) were all significantly increased in the obese rats' kidneys. There were no differences for the sodium hydrogen exchanger (NHE3), the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2 or BSC1), the type II sodium-phosphate cotransporter (NaPi-2), or the alpha-subunit of ENaC. These selective increases could possibly increase sodium retention by the kidney and therefore could play a role in obesity-related hypertension.
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PMID:Increased renal Na-K-ATPase, NCC, and beta-ENaC abundance in obese Zucker rats. 1155 10

Vasopressin plays a role in both salt and water balance in the kidney. Classic studies, utilizing isolated perfused tubules, have revealed that vasopressin increases sodium reabsorption in the kidney thick ascending limb and the collecting duct. Furthermore, the activity of several sodium transport proteins expressed in these segments, such as the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and the epithelial sodium channel (ENaC), have been shown to be directly increased by vasopressin. Increased protein abundance might be one means through which sodium transporter and channel activity is enhanced. We have used immunoblotting and immunohistochemistry in order to investigate the regulation of abundance of the major sodium transporters and channels expressed along the renal tubule in response to vasopressin. Chronic (7-day) studies were performed in which vasopressin levels were elevated either endogenously by water restriction of Sprague-Dawley rats or exogenously through infusion of the vasopressin V2-receptor-selective agonist, dDAVP (1-deamino-8d-arginine-vasopressin), to Brattleboro rats. We found a significant increase in protein abundance for NKCC2 and the beta- and gamma-subunits of ENaC with either water restriction or dDAVP infusion. The alpha-subunit of Na-K-ATPase was increased by water restriction, but not by dDAVP infusion, and alpha-ENaC and the thiazide-sensitive cotransporter (NCC) were increased by dDAVP infusion but not by water restriction. Acute (60-min) in vivo exposure to dDAVP led to an increase in both beta- and gamma-ENaC abundance in kidney cortex homogenates, displaying the rapid nature of some of these changes. Overall these increases in sodium transporter and channel abundances likely contribute to both the antidiuretic and antinatriuretic actions of vasopressin.
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PMID:Regulation of the abundance of renal sodium transporters and channels by vasopressin. 1157 75

Aldosterone controls extracellular volume and blood pressure by regulating Na+ reabsorption, in particular by epithelia of the distal nephron. A main regulatory site of this transcellular transport is the epithelial sodium channel (ENaC) that mediates luminal Na+ influx. The Na,K-ATPase (Na+ pump) that coordinately extrudes Na+ across the basolateral membrane is known to be regulated by short term aldosterone as well. We now show that in the cortical collecting duct (CCD) from adrenalectomized rats, the increase in Na,K-ATPase activity (approximately 3-fold in 3 h), induced by a single aldosterone injection, can be fully accounted by the increase in Na,K-ATPase cell surface expression (+ 497 +/- 35%). The short term aldosterone action was further investigated in cultured mouse collecting duct principal cells mpkCCD(cl4). Within 2 h, maximal Na,K-ATPase function assessed by Na+ pump current (I(p)) measurements and Na,K-ATPase cell surface expression were increased by 20-50%. Aldosterone did not modify the Na+ dependence of the Na+ pumps and induced transcription- and translation-dependent actions on pump surface expression and current independently of ENaC-mediated Na+ influx. In summary, short term aldosterone directly increases the cell surface expression of pre-existing Na+ pumps in kidney CCD target cells. Thus, aldosterone controls Na+ reabsorption in the short term not only by regulating the apical cell surface expression of ENaC (Loffing, J., Zecevic, M., Feraille, E., Kaissling, B., Asher, C., Rossier, B. C., Firestone, G. L., Pearce, D., and Verrey, F. (2001) Am. J. Physiol. 280, F675-F682) but also by coordinately acting on the basolateral cell surface expression of the Na,K-ATPase.
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PMID:Short term effect of aldosterone on Na,K-ATPase cell surface expression in kidney collecting duct cells. 1159 18

Upregulation of the colonic H(+)-K(+)- ATPase (cHKA) during hyperaldosteronism suggests that it functions in both K(+) conservation and electrogenic Na(+) absorption in the colon when Na(+)-conserving mechanisms are activated. To test this hypothesis, wild-type (cHKA(+/+)) and cHKA-deficient (cHKA(-/-)) mice were fed Na(+)-replete and Na(+)-restricted diets and their responses were analyzed. In both genotypes, Na(+) restriction led to reduced plasma Na(+) and increased serum aldosterone, and mRNAs for the epithelial Na(+) channel (ENaC) beta- and gamma-subunits, channel-inducing factor, and cHKA were increased in distal colon. Relative to wild-type controls, cHKA(-/-) mice on a Na(+)-replete diet had elevated fecal K(+) excretion. Dietary Na(+) restriction led to increased K(+) excretion in knockout but not in wild-type mice. The amiloride-sensitive, ENaC-mediated short-circuit current in distal colon was significantly reduced in knockout mice maintained on either the Na(+)-replete or Na(+)-restricted diet. These results demonstrate that cHKA plays an important role in K(+) conservation during dietary Na(+) restriction and suggest that cHKA-mediated K(+) recycling across the apical membrane is required for maximum electrogenic Na(+) absorption.
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PMID:Colonic H(+)-K(+)-ATPase in K(+) conservation and electrogenic Na(+) absorption during Na(+) restriction. 1170 41


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