Alveolar Type 1 Cells Express the α2 Na,K-ATPase, Which Contributes to Lung Liquid Clearance

Ridge, Karen M.; Olivera, Walter; Saldías, Fernando; Azzam, Zaher S.; Horowitz, Stuart; Rutschman, David H.; Dumasius, Vidas; Sznajder, Jacob I.

doi:10.1161/01.res.0000059414.10360.f2

Cited by 117 publications

(109 citation statements)

References 44 publications

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“…Adenovirus Infection Protocol-Rats were anesthetized with 40 mg/kg Nembutal intraperitoneally and orally intubated with a 14-gauge plastic catheter prior to adenoviral infection (15). Three experimental groups were studied: Sham-surfactant (n ϭ 6), Adnull (n ϭ 8), and AdSOD2 (n ϭ 10).…”

Section: Methodsmentioning

confidence: 99%

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

Litvan

Briva

Wilson

et al. 2006

Journal of Biological Chemistry

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Hypoxia has been shown to cause lung edema and impair lung edema clearance. In the present study, we exposed isolated rat lungs to pO 2 ‫؍‬ 40 mm Hg for 60 min or rats to 8% O 2 for up to 24 h and then measured changes in alveolar fluid reabsorption (AFR) and Na,K-ATPase function. Low levels of oxygen severely impaired AFR in both ex vivo and in vivo models. The decrease in AFR was associated with a decrease in Na,K-ATPase activity and protein abundance in the basolateral membranes from peripheral lung tissue of hypoxic rats. ␤-Adrenergic agonists restored AFR in rats exposed to 8% O 2 (from 0.02 ؎ 0.07 ml/h to 0.59 ؎ 0.03 ml/h), which was associated with parallel increases in Na,K-ATPase protein abundance in the basolateral membrane. Hypoxia is associated with increased production of reactive oxygen species. Therefore, we examined whether overexpression of SOD2, manganese superoxide dismutase, would prevent the hypoxia-mediated decrease in AFR. Spontaneously breathing rats were infected with a replication-deficient human type 5 adenovirus containing cDNA for SOD2. An otherwise identical virus that contained no cDNA was used as a control (Adnull). Hypoxic Adnull rats had decreased rates of AFR (0.12 ؎ 0.1 ml/h) as compared with hypoxic AdSOD2 and normoxic control rats (0.47 ؎ 0.04 ml/h and 0.49 ؎ 0.02 ml/h, respectively), with parallel changes in Na,K-ATPase.Severe hypoxia can occur during ascent to high altitude (1) and in patients with acute respiratory distress syndrome and pulmonary edema. One of the primary defense mechanisms in the lung against alveolar fluid accumulation is the active transport of sodium out of the air spaces, which generates a transepithelial osmotic gradient that leads to alveolar fluid reabsorption (AFR).2 Sodium enters the apical membrane of alveolar epithelial cells through amiloride-sensitive Na ϩ channels (2, 3) and is then transported out across the basolateral membrane by the ouabain-inhibitable Na,K-ATPase (4 -7). Hypoxia has been shown to impair AFR and may contribute to alveolar fluid accumulation (8, 9). However, the mechanisms by which hypoxia impairs AFR and alveolar epithelial sodium transport proteins has not been fully elucidated.A mechanism by which hypoxia might impair AFR is by altering the function of either apical epithelial sodium channels and/or basolateral Na,K-ATPase proteins. Several in vitro studies using cultured alveolar epithelial cells have demonstrated that exposure to hypoxia results in the decrease in epithelial sodium channels and Na,K-ATPase protein abundance (10 -12), which was reversed upon reoxygenation. Other investigators have reported various mechanisms associated with the decrease in alveolar fluid reabsorption in animals exposed to hypoxia in vivo (9,11,13).In the current study, we provide evidence that exposure to hypoxia results in decreased Na,K-ATPase activity and protein abundance at the plasma membrane, which contributes to a decrease in alveolar fluid reabsorption in both in vivo and ex vivo models of hypoxia. These data suggest that (a...

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Section: Methodsmentioning

confidence: 99%

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

Litvan

Briva

Wilson

et al. 2006

Journal of Biological Chemistry

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“…ATII cells were isolated from the lungs of male Sprague-Dawley rats by elastase digestion and culture in DMEM (Vagin et al, 2005;Ridge et al, 2003). The day of isolation and plating of rATII on transwell inserts was designated day 0.…”

Section: Adenoviral Infectionmentioning

confidence: 99%

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

Tokhtaeva

Sun

Deiss-Yehiely

et al. 2016

Journal of Cell Science

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FXYD5 (also known as dysadherin), a regulatory subunit of the Na,K-ATPase, impairs intercellular adhesion by a poorly understood mechanism. Here, we determined whether FXYD5 disrupts the transdimerization of Na,K-ATPase molecules located in neighboring cells. Mutagenesis of the Na,K-ATPase β 1 subunit identified four conserved residues, including Y199, that are crucial for the intercellular Na,K-ATPase trans-dimerization and adhesion. Modulation of expression of FXYD5 or of the β 1 subunit with intact or mutated β 1 -β 1 binding sites demonstrated that the anti-adhesive effect of FXYD5 depends on the presence of Y199 in the β 1 subunit. Immunodetection of the plasma membrane FXYD5 was prevented by the presence of O-glycans. Partial FXYD5 deglycosylation enabled antibody binding and showed that the protein level and the degree of O-glycosylation were greater in cancer than in normal cells. FXYD5-induced impairment of adhesion was abolished by both genetic and pharmacological inhibition of FXYD5 O-glycosylation. Therefore, the extracellular O-glycosylated domain of FXYD5 impairs adhesion by interfering with intercellular β 1 -β 1 interactions, suggesting that the ratio between FXYD5 and α 1 -β 1 heterodimer determines whether the Na,K-ATPase acts as a positive or negative regulator of intercellular adhesion.

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“…A g-subunit can provide further tissue-specific regulation (18,19). In the lung, the Na,K-ATPase localizes at basolateral surface of ATI and ATII cells (20), moving three Na 1 ions out of the cell and two K 1 ions into the cell per ATP molecule consumed. The main function of the Na 1 -pump is the regulation of intracellular Na 1 concentration, which with other transporters regulates cell volume, as well as glucose and amino acid transport (21).…”

Section: Regulation Of the Nak-atpasementioning

confidence: 99%

Role of Ubiquitination in Na,K-ATPase Regulation during Lung Injury

Helenius

Dada

Sznajder

2010

Proceedings of the American Thoracic Society

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During acute lung injury edema accumulates in the alveolar space, resulting in hypoxemia due to intrapulmonary shunt. The alveolar Na,K-ATPase, by effecting active Na 1 transport, is essential for removing edema from the alveolar spaces. However, during hypoxia it is endocytosed and degraded, which results in decreased Na,KATPase function and impaired lung edema clearance. Na,K-ATPase endocytosis and degradation require the phosphorylation and subsequent ubiquitination of the Na,K-ATPase. These events are the results of cross-talk between post-translational modifications, and how ubiquitination of a specific protein can result from injurious extracellular stimuli. Here, we review current knowledge on the regulation of Na,K-ATPase activity during lung injury, focusing on the role of Na,K-ATPase ubiquitination during hypoxia. A better understanding of these signaling pathways can be of relevance for the design of novel treatments to ameliorate the deleterious effects of acute lung injury.

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Alveolar Type 1 Cells Express the α2 Na,K-ATPase, Which Contributes to Lung Liquid Clearance

Cited by 117 publications

References 44 publications

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

Role of Ubiquitination in Na,K-ATPase Regulation during Lung Injury

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