HYPOXIA DOWN-REGULATES EXPRESSION AND ACTIVITY OF EPITHELIAL SODIUM-CHANNELS IN RAT ALVEOLAR EPITHELIAL-CELLS

Decrease in alveolar oxygen tension may induce acute lung injury with pulmonary edema. We investigated whether, in alveolar epithelial cells , expression and activity of epithelial sodium (Na) channels and Na,K- adenosine triphosphatase, the major components of transepithelial Na t ransport, were regulated by hypoxia. Exposure of cultured rat alveolar cells to 3% and 0% O-2 for 18 h reduced Na channel activity estimated by amiloride-sensitive Na-22 influx by 32% and 67%, respectively, whe reas 5% O-2 was without effect. The decrease in Na channel activity in duced by 0% O-2 was time-dependent, significant at 3 h of exposure and maximal at 12 and 18 h. It was associated with a time-dependent decli ne in the amount of mRNAs encoding the alpha-, beta-, and gamma-subuni ts of the rat epithelial Na channel (rENaC) and with a 32% decrease in alpha-rENaC protein synthesis as evaluated by immunoprecipitation aft er 18 h of exposure. The 0% O-2 hypoxia also caused a time-dependent d ecrease in (1) ouabain-sensitive (86)Rubidium influx in intact cells, (2) the maximal velocity of Na,K-ATPase on crude homogenates, and (3) alpha(1)- and beta(1)-Na,K-ATPase mRNA levels. Levels of rENaC and alp ha(1)-Na,K-ATPase mRNA returned to control values within 48 h of reoxy genation, and this was associated with complete functional recovery. W e conclude that hypoxia induced a downregulation of expression and act ivity of epithelial Na channels and Na,K-ATPase in alveolar cells. Sub sequent decrease in Na reabsorption by alveolar epithelium could parti cipate in the maintenance of hypoxia-induced alveolar edema.