Am J Physiol Lung Cell Mol Physiol 2007 Dec 01;2936:L1454-62. doi: 10.1152/ajplung.00248.2007.

ENaC alpha-subunit variants are expressed in lung epithelial cells and are suppressed by oxidative stress.

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Amiloride-sensitive epithelial sodium channel (ENaC) is a major sodium channel in the lung facilitating fluid absorption. ENaC is composed of alpha-, beta-, and gamma-subunits, and the alpha-subunit is indispensable for ENaC function in the lung. In human lungs, the alpha-subunit is expressed as various splice variants. Among them, alpha(1)- and alpha(2)-subunits are two major variants with different upstream regulatory sequences that possess similar channel characteristics when tested in Xenopus oocytes. Despite the importance of alpha-ENaC, little was known about the relative abundance of its variants in lung epithelial cells. Furthermore, lung infection and inflammation are often accompanied by reduced alpha-ENaC expression, oxidative stress, and pulmonary edema. However, it was not clear how oxidative stress affects expression of alpha-ENaC variants. In this study, we examined relative expression levels of alpha-subunit variants in four human lung epithelial cell lines. We also tested the hypothesis that oxidative stress inhibits alpha-ENaC expression. Our results show that both alpha(1)- and alpha(2)-ENaC variants are expressed in the cells we tested, but relative abundance varies. In the two monolayer-forming cell lines, H441 and Calu-3, alpha(2)-ENaC is the predominant variant. We also show that H(2)O(2) specifically suppresses alpha(1)- and alpha(2)-ENaC variant expression in H441 and Calu-3 cells in a dose-dependent fashion. This suppression is achieved by inhibition of their promoters and is attenuated by dexamethasone. These data demonstrate the importance of the alpha(2)-subunit variant and suggest that glucocorticoids and antioxidants may be useful in correcting infection/inflammation-induced lung fluid imbalance.

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Species referenced: Xenopus
Genes referenced: calu scnn1a