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

¹McGuire Veterans Affairs Medical Center and ²Department of Physiology, Virginia Commonwealth University, Richmond, Virginia

Submitted 28 June 2007 ; accepted in final form 26 September 2007

Amiloride-sensitive epithelial sodium channel (ENaC) is a major sodium channel in the lung facilitating fluid absorption. ENaC is composed of -, β-, and -subunits, and the -subunit is indispensable for ENaC function in the lung. In human lungs, the -subunit is expressed as various splice variants. Among them, ₁- and 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 -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 -ENaC expression, oxidative stress, and pulmonary edema. However, it was not clear how oxidative stress affects expression of -ENaC variants. In this study, we examined relative expression levels of -subunit variants in four human lung epithelial cell lines. We also tested the hypothesis that oxidative stress inhibits -ENaC expression. Our results show that both ₁- and 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, ₂-ENaC is the predominant variant. We also show that H₂O₂ specifically suppresses ₁- and 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 ₂-subunit variant and suggest that glucocorticoids and antioxidants may be useful in correcting infection/inflammation-induced lung fluid imbalance.

ion channel; steroids; transcription; promoter; splice variant