Genetic variation of αENaC influences lung diffusion during exercise in humans

Abstract

Exercise, decompensated heart failure, and exposure to high altitude have been shown to cause symptoms of pulmonary edema in some, but not all, subjects, suggesting a genetic component to this response. Epithelial Na+ Channels (ENaC) regulate Na+ and fluid reabsorption in the alveolar airspace in the lung. An increase in number and/or activity of ENaC has been shown to increase lung fluid clearance. Previous work has demonstrated common functional genetic variants of the α-subunit of ENaC, including an A→T substitution at amino acid 663 (αA663T). We sought to determine the influence of the T663 variant of αENaC on lung diffusion at rest and at peak exercise in healthy humans. Thirty healthy subjects were recruited for study and grouped according to their SCNN1A genotype [n= 17vs.13, age=25±7vs.30±10yrs., BMI= 23±4vs.25±4kg/m2, V̇O2peak= 95±30vs.100±31%pred., mean±SD, for AA (homozygous for αA663) vs. AT/TT groups (at least one αT663), respectively]. Measures of the diffusing capacity of the lungs for carbon monoxide (DLCO), the diffusing capacity of the lungs for nitric oxide (DLNO), alveolar volume (VA), and alveolar-capillary membrane conductance (DM) were taken at rest and at peak exercise. Subjects expressing the AA polymorphism of ENaC showed a significantly greater percent increase in DLCO and DLNO, and a significantly greater decrease in systemic vascular resistance from rest to peak exercise than those with the AT/TT variant (DLCO=51±12vs.36±17%, DLNO=51±24vs.32±25%, SVR=−67±3vs.−50±8%, p<0.05). The AA ENaC group also tended to have a greater percent increase in DLCO/VA from rest to peak exercise, although this did not reach statistical significance (49±26vs.33±26%, p=0.08). These results demonstrate that genetic variation of the α-subunit of ENaC at amino acid 663 influences lung diffusion at peak exercise in healthy humans, suggesting differences in alveolar Na+ and, therefore, fluid handling. These findings could be important in determining who may be susceptible to pulmonary edema in response to various clinical or environmental conditions.

Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis

“…NPD is a validated measure of ion channel activity and the fact that there was a relationship between EBC and NPD helps to validate EBC as a measure of changes in ASL ion concentration and as such an indirect measure of ion channel activity. Also we have previously found that 1)there is a relationship between EBC Na + and epithelial sodium channel genotypes, where the less active ENaC genotype demonstrated lower EBC Na + values 50 ; 2) CF subjects have lower EBC Cl − at baseline than healthy subjects as would be expected and ENaC genotype influences lung diffusion capacity 51 . Collectively, these findings strengthen the claim that EBC can be utilized as a measure of ion channel activity.…”

Mapping allosteric linkage to channel gating by extracellular domains in the human epithelial sodium channel

“…Therefore, the ENaC/Degenerin ion channel family is crucial to electrolyte homeostasis in organs such as the kidney, the lung, and the brain [3]. Mutations in channel subunits can cause severe electrolyte disorders, such as hereditary hypertension Liddle syndrome and neuronal degeneration in C. elegans [1,[3][4][5][6][7][8].…”

Genetic Variation of SCNN1A Influences Lung Diffusing Capacity in Cystic Fibrosis

“…In humans, the αT663 variant has been associated with hypertension, suggesting its increased channel activity resulted in increased Na + reabsorption in the kidneys (2). Genetic variation of SCNN1A has also previously been shown to influence the diffusing capacity of the lungs in response to β 2 -adrenergic stimulation (3). Healthy individuals with the αA663 ENaC variant demonstrated a greater increase in lung diffusing capacity in response to exercise as compared to those with at least one copy of the αT663 variant (3).…”