Hypoxia reduces airway epithelial sodium transport in rats

Tomlinson, Laurie; Carpenter, Todd; Baker, Emma; Bridges, J. B.; Weil, John V.

doi:10.1152/ajplung.1999.277.5.l881

Cited by 21 publications

(21 citation statements)

References 17 publications

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“…Consistent with this hypothesis, inhibition of the Na-K-ATPase by ouabain decreases nasal PD in the rat [26]. Moreover, in mice, Na-K-ATPase activity represents a potential limiting step in respiratory transepithelial sodium transport [10], and, in the rat, hypoxia decreases nasal PD [26], alveolar fluid clearance and Na-K-ATPase function [27]. However, since ENaC and Na-K-ATPase work in series, one would expect that impairment of Na-K-ATPase function increases intracellular sodium and, in turn, results in a reduced gradient for Na z entry.…”

Section: Discussionsupporting

confidence: 62%

“…The present authors speculate that in the subjects in this study, the altitude-induced impairment of the transepithelial sodium transport was related to a defect in sodium extrusion. Consistent with this hypothesis, inhibition of the Na-K-ATPase by ouabain decreases nasal PD in the rat [26]. Moreover, in mice, Na-K-ATPase activity represents a potential limiting step in respiratory transepithelial sodium transport [10], and, in the rat, hypoxia decreases nasal PD [26], alveolar fluid clearance and Na-K-ATPase function [27].…”

Section: Discussionmentioning

confidence: 75%

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High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

Sartori¹,

Duplain²,

Lepori³

et al. 2004

Eur Respir J

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High-altitude pulmonary oedema (HAPE) occurs in predisposed individuals at altitudes w2,500 m. Defective alveolar fluid clearance secondary to a constitutive impairment of the respiratory transepithelial sodium transport contributes to its pathogenesis. Hypoxia impairs the transepithelial sodium transport in alveolar epithelial type II cells in vitro. If this impairment is also present in vivo, high-altitude exposure could aggravate the constitutive defect in sodium transport in HAPE-prone subjects, and thereby further facilitate pulmonary oedema.Therefore, the aim of the current study was to measure the nasal potential difference (PD) in 21 HAPE-prone and 29 HAPE-resistant subjects at low altitude and 30 h after arrival at high altitude (4,559 m).High-altitude exposure significantly decreased the mean¡SD nasal PD in HAPEprone (18.0¡6.2 versus 12.5¡6.8 mV) but not in HAPE-resistant subjects (25.6¡9.4 versus 22.9¡9.2 mV). This altitude-induced decrease was not associated with an altered amiloride-sensitive fraction, but was associated with a significantly lower amilorideinsensitive fraction of the nasal PD.These findings provide evidence in vivo that an environmental factor may impair respiratory transepithelial sodium transport in humans. They are consistent with the concept that in high-altitude pulmonary oedema-susceptible subjects, the combination of a constitutive and an acquired defect in this transport mechanism facilitates the development of pulmonary oedema during high-altitude exposure. High-altitude pulmonary oedema (HAPE) is a lifethreatening condition that occurs in predisposed but otherwise healthy individuals at altitudes w2,500 m. Augmented alveolar fluid flooding related to exaggerated hypoxic pulmonary vasoconstriction plays an important role in its pathogenesis, secondary to endothelial dysfunction and sympathetic overactivity [1][2][3]. However, recent observations indicate that this mechanism may not be sufficient to cause high-altitude pulmonary oedema [4].Active sodium transport across the alveolar epithelium plays an important role in keeping the lungs free of fluid [5,6]. In alveolar epithelial cells, sodium enters the apical membrane primarily through the amiloride-sensitive cation channels (mainly ENaC), and is then transported across the basolateral membrane into the interstitium by the ouabain-inhibitable Na-K-ATPase [5][6][7][8].A genetic impairment of the transepithelial sodium transport mechanism facilitates pulmonary oedema in transgenic mice [9,10] and possibly also in humans, as suggested by HAPE-prone subjects who have a smaller nasal potential difference (PD) (an indirect marker of vectorial sodium transport in the distal airways) [11] than mountaineers resistant to this condition [12]. Consistent with this concept, prophylactic stimulation of this transport mechanism with the b 2 -adrenergic agonist salmeterol, at a dose that stimulates respiratory sodium transport in vitro [8] and increases alveolar fluid clearance in vivo [13], decreased the incidence of HAPE in h...

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 75%

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

Sartori¹,

Duplain²,

Lepori³

et al. 2004

Eur Respir J

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“…While there may be important methodological differences between the present experiments and those using lung cells, the sensitivity to low O 2 that we report here is probably physiologically relevant. One group of investigators (13,51) The second feature of the present experiments is that higher than "normal" levels of O 2 can increase ENaC function. This effect is evident for values up to 40% O 2 ; 95% O 2 did not consistently produce any further increase in Na transport (Fig.…”

Section: Discussionmentioning

confidence: 73%

Oxygen regulation of the epithelial Na channel in the collecting duct

Husted

Sigmund

et al. 2011

American Journal of Physiology-Renal Physiology

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The PO 2 within the kidney changes dramatically from cortex to medulla. The present experiments examined the effect of changing PO 2 on epithelial Na channel (ENaC)-mediated Na transport in the collecting duct using the mpkCCD-c14 cell line. Decreasing ambient O 2 concentration from 20 to 8% decreased ENaC activity by 40%; increasing O2 content to 40% increased ENaC activity by 50%. The O 2 effect required several hours to develop and was not mimicked by the acid pH that developed in monolayers incubated in low-O2 medium. Corticosteroids increased ENaC activity at each O 2 concentration; there was no interaction. The pathways for O2 and steroid regulation of ENaC are different since O2 did not substantially affect Sgk1, ␣-ENaC, Gilz, or Usp2-45 mRNA levels, genes involved in steroid-mediated ENaC regulation. The regulation of ENaC activity by these levels of O2 appears not to be mediated by changes in hypoxia-inducible factor-1␣ or -2␣ activity or a change in AMP kinase activity. Changes in O2 concentration had minimal effect on ␣-or ␥-ENaC mRNA and protein levels; there were moderate effects on ␤-ENaC levels. However, 40% O2 induced substantially greater total ␤-and ␥-ENaC on the apical surface compared with 8% O2; both subunits demonstrated a greater increase in the mature forms. The ␣-ENaC subunit was difficult to detect on the apical surface, perhaps because our antibodies do not recognize the major mature form. These results identify a mechanism of ENaC regulation that may be important in different regions of the kidney and in responses to changes in dietary NaCl.heat shock protein-70; heme oxygenase; adenosine 5=-monophosphate kinase; hypoxia-inducible factor-1␣; corticosteroids; surface expression THE OXYGEN TENSION OF THE renal parenchyma varies from that approaching the PO 2 of arterial blood near the surface of the kidney to considerably lower values in the midcortex (35). The PO 2 of the inner medulla is substantially below that of almost all normal tissues with values of 10 -15 Torr being routinely measured (4, 35). The relatively low PO 2 in both the cortex and the medulla is the result of a functional countercurrent exchange between arterioles and venules. The lower PO 2 in the medulla is believed to predispose to tubular injury in the setting of acute hemodynamic compromise, but the physiological consequences of the widely varying PO 2 of different regions is poorly understood.The collecting duct traverses the axis of the kidney from cortex to papillary tip and, consequently, is exposed to a wide range of PO 2 . It is well known that the rate of Na absorption by the cortical collecting duct is considerably greater than that by the medullary collecting duct (19,48). The reason for this regional difference in Na transport rate is not clear. Two possibilities have been proposed: hypertonicity and the high concentration of transforming growth factor-␤ within the renal medulla (28). Another possibility is the O 2 tension: low PO 2 in lung epithelial cells reduces epithelial Na channel (ENaC) activity (...

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“…Also, an endogenous ouabain-like compound has been found to be increased in high altitude in human plasma (80, 107, 108). One experimental study in rats that reported a reduction in airway epithelial sodium transport from hypoxia supported this hypothesis as well (352).…”

Section: B Hypoxiamentioning

confidence: 86%

Lung Epithelial Fluid Transport and the Resolution of Pulmonary Edema

Matthay

Folkesson²,

Clérici³

2002

Physiological Reviews

611

649

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The discovery of mechanisms that regulate salt and water transport by the alveolar and distal airway epithelium of the lung has generated new insights into the regulation of lung fluid balance under both normal and pathological conditions. There is convincing evidence that active sodium and chloride transporters are expressed in the distal lung epithelium and are responsible for the ability of the lung to remove alveolar fluid at the time of birth as well as in the mature lung when pathological conditions lead to the development of pulmonary edema. Currently, the best described molecular transporters are the epithelial sodium channel, the cystic fibrosis transmembrane conductance regulator, Na+-K+-ATPase, and several aquaporin water channels. Both catecholamine-dependent and -independent mechanisms can upregulate isosmolar fluid transport across the distal lung epithelium. Experimental and clinical studies have made it possible to examine the role of these transporters in the resolution of pulmonary edema.

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Hypoxia reduces airway epithelial sodium transport in rats

Cited by 21 publications

References 17 publications

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

Oxygen regulation of the epithelial Na channel in the collecting duct

Lung Epithelial Fluid Transport and the Resolution of Pulmonary Edema

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