Structure and Hormone Responsiveness of the Gene Encoding the α -Subunit of the Rat Amiloride-Sensitive Epithelial Sodium Channel

Otulakowski, Gail; Rafii, Bijan; Bremner, Harry Robert; O’Brodovich, Hugh

doi:10.1165/ajrcmb.20.5.3382

Cited by 63 publications

(75 citation statements)

References 59 publications

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“…Dex upregulates ENaC expression via a very conserved GRE in the ␣ENaC promoter (17,63,74). As with mRNA expression, Dex treatment increased Luc activity by fivefold in the cells, and this increase was sensitive to TNF.…”

Section: Discussionmentioning

confidence: 94%

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Dexamethasone inhibits the action of TNF on ENaC expression and activity

Dagenais

Fréchette²,

Clermont³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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We have reported that TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na+channel (ENaC) by ∼70% in alveolar epithelial cells. Because dexamethasone has been shown to upregulate ENaC mRNA expression and is well known to downregulate proinflammatory genes, we tested if it could alleviate the effect of TNF on ENaC expression and activity. In cotreatment with TNF, we found that dexamethasone reversed the inhibitory effect of TNF and upregulated α, β, and γENaC mRNA expression. When the cells were pretreated for 24 h with TNF before cotreatment, dexamethasone was still able to increase αENaC mRNA expression to 1.8-fold above control values. However, in these conditions, β and γENaC mRNA expression was reduced to 47% and 14%, respectively. The potential role of TNF and dexamethasone on αENaC promoter activity was tested in A549 alveolar epithelial cells. TNF decreased luciferase (Luc) expression by ∼25% in these cells, indicating that the strong diminution of αENaC mRNA must be related to posttranscriptional events. Dexamethasone raised Luc expression by fivefold in the cells and augmented promoter activity by 2.77-fold in cotreatment with TNF. In addition to its effect on αENaC gene expression, dexamethasone was able to maintain amiloride-sensitive current as well as the liquid clearance abilities of TNF-treated cells within the normal range. All these results suggest that dexamethasone alleviates the downregulation of ENaC expression and activity in TNF-treated alveolar epithelial cells.

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Section: Discussionmentioning

confidence: 94%

“…Dexamethasone (Dex) is a synthetic steroid that has been shown to upregulate ENaC expression via a very conserved glucocorticoid regulatory element (GRE) in its promoter (15,17,63,74). Dex is also a well-known anti-inflammatory agent that has been used or proposed as a therapeutic approach to inflammatory disease, including lung injury (29).…”

mentioning

confidence: 99%

Dexamethasone inhibits the action of TNF on ENaC expression and activity

Dagenais

Fréchette²,

Clermont³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…NAC can replete the intracellular GSH lost owing to its oxidation by ROS or peroxynitrite (25), an adduct of NO reactions with ROS, or alternatively modulate transcription factors such as NF-B and AP-1, which are known to be involved in cellular oxidative response (26). There are NF-B and activator protein-1 (AP-1) sites on the promoter of ␣rENaC (27).…”

Section: Discussionmentioning

confidence: 99%

Preventing Endotoxin-Stimulated Alveolar Macrophages from Decreasing Epithelium Na+ Channel (ENaC) mRNA Levels and Activity

et al. 2000

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The acute respiratory distress syndrome is characterized by impairment of the alveolar-capillary barrier. Our laboratory has shown that distal lung epithelial cell (DLEC) amiloride-sensitive Na ϩ transport is impaired by in vitro coculture with endotoxin (lipopolysaccharide)-stimulated alveolar macrophages (AM) through an L-arginine-dependent mechanism. To investigate the effect of this model on mRNA levels of the rat epithelial Na ϩ channel, mature fetal rat DLEC monolayers were incubated for 16 h with rat AM (1 ϫ 10 7 ) and lipopolysaccharide (10 g/mL), or the cell-free supernatant of lipopolysaccharide-stimulated rat AM. Such exposure resulted in a profound decrease in mRNA expression for all subunits (␣, ␤, and ␥) of the rat epithelial Na ϩ channel, without affecting 18S RNA levels. This effect was prevented by the antioxidant N-acetylcysteine. In separate experiments, confluent DLEC monolayers were exposed to lipopolysaccharide-stimulated AM supernatant for 16 h with or without N-acetylcysteine and DTT and studied in Ussing chambers. As previously demonstrated in our laboratory, AM supernatant resulted in a significant (p Ͻ 0.05) impairment of DLEC Na Abbreviations AM, alveolar macrophages ARDS, adult respiratory distress syndrome ALI, acute lung injury DLEC, distal lung epithelial cells ENaC, epithelial sodium channel FBS, fetal bovine serum GSH, glutathione I sc , short-circuit current LPS, lipopolysaccharide MEM, minimum essential medium NAC, N-acetyl cysteine NAME, N -nitro-L-arginine methyl ester NO, nitric oxide PD, transepithelial potential difference rENaC, rat epithelial sodium channel ROS, reactive oxygen species ARDS, or ALI, represents an important cause of mortality in critically ill patients (1). Both direct lung injury and distant insults (1), most commonly nonpulmonary sepsis, can initiate a process resulting in a fundamental derangement of the intrinsic barrier property of the lung, manifested clinically as highpermeability pulmonary edema, which is one characteristic of ARDS. It is widely held that these devastating changes most commonly arise because of widespread and uncontrolled activation of inflammatory cells, including neutrophils and macrophages, with the release of a wide range of potentially injurious mediators, such as cytokines, proteolytic enzymes, biologically active lipids, and ROS (2). Activation of inflammatory cells could, in turn, have deleterious effects on the ability of alveolar epithelia to clear edema fluid.The failure of the alveolar-capillary membrane, the structure responsible for preserving a fluid-free alveolar space vital for adequate gas exchange, has been the focus of increasing attention in continuing efforts to understand the basic mechanisms

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“…Champigny et al (21) also reported no effect of thyroid hormones on ENaC mRNA expression but did report a potentiation by thyroid hormones of the steroid effect on Na ϩ currents in rat alveolar epithelial cells. Otulakowski et al (53) have subsequently identified putative binding sites for thyroid and glucocorticoid receptors in the promoter region of ␣-ENaC, and, although T 3 alone had no effect on reporter gene activity, it potentiated gene stimulation by steroid hormones. These synergistic effects of steroid and thyroid hormones echo their role in the maturation of the epinephrine response and its interaction with oxygen.…”

Section: Hormonal Regulation Of Maturation Of the Epinephrine Responsementioning

confidence: 99%

Invited Review: Clearance of lung liquid during the perinatal period

Barker

Olver

2002

Journal of Applied Physiology

105

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Barker, Pierre M., and Richard E. Olver. Invited Review: Clearance of lung liquid during the perinatal period. J Appl Physiol 93: 1542-1548, 2002; 10.1152/japplphysiol.00092.2002.-At birth, the distal lung epithelium undergoes a profound phenotypic switch from secretion to absorption in the course of adaptation to air breathing. In this review, we describe the developmental regulation of key membrane transport proteins and the way in which epinephrine, oxygen, glucocorticoids, and thyroid hormones interact to bring about this crucial change in function. Evidence from molecular, transgenic, cell culture, and whole lung studies is presented, and the clinical consequences of the failure of the physiological mechanisms that underlie perinatal lung liquid absorption are discussed. lung liquid; sodium absorption; chloride secretion; epithelial sodium channel; cystic fibrosis transmembrane conductance regulator THE MECHANISMS RESPONSIBLE for lung liquid clearance during the neonatal period develop gradually during the latter part of the third trimester of pregnancy, but the phenotypic switch of the lung epithelium from net secretion to net absorption, triggered by events at birth, is sudden. Although lung liquid absorption at birth is "a performance without rehearsal," the lung may be called on for an encore in later life when these same mechanisms are activated to clear accumulated edema liquid.Many of the early studies of perinatal lung liquid clearance, which were mostly undertaken on the intact lungs of rabbits and sheep in the 1970s and 1980s, provided information in vivo on the time course and regulation of lung liquid clearance in a fully integrated physiological context. These data have been supported and augmented in the past decade by cloning of genes that regulate transepithelial ion transport [particularly the sodium pump (Na ϩ -K ϩ -ATPase) and the epithelial Na ϩ channel (ENaC)] and the use of molecular approaches that have uncovered information at a subcellular level.

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Structure and Hormone Responsiveness of the Gene Encoding the α -Subunit of the Rat Amiloride-Sensitive Epithelial Sodium Channel

Cited by 63 publications

References 59 publications

Dexamethasone inhibits the action of TNF on ENaC expression and activity

Dexamethasone inhibits the action of TNF on ENaC expression and activity

Preventing Endotoxin-Stimulated Alveolar Macrophages from Decreasing Epithelium Na+ Channel (ENaC) mRNA Levels and Activity

Invited Review: Clearance of lung liquid during the perinatal period

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