The role of hypoxia-induced modulation of alveolar epithelial Na(+)- transport in hypoxemia at high altitude

Reabsorption of excess alveolar fluid is driven by vectorial Na(+)-transport across alveolar epithelium, which protects from alveolar flooding and facilitates gas exchange. Hypoxia inhibits Na(+)-reabsorption in cultured cells and in-vivo by decreasing activity of epithelial Na(+)-channels (ENaC), which impairs alveolar fluid clearance. Inhibition also occurs during in-vivo hypoxia in humans and laboratory animals. Signaling mechanisms that inhibit alveolar reabsorption are poorly understood. Because cellular adaptation to hypoxia is regulated by hypoxia-inducible transcription factors (HIF), we tested whether HIFs are involved in decreasing Na(+)-transport in hypoxic alveolar epithelium. Expression of HIFs was suppressed in cultured rat primary alveolar epithelial cells (AEC) with shRNAs. Hypoxia (1.5% O(2), 24 h) decreased amiloride-sensitive transepithelial Na(+)-transport, decreased the mRNA expression of α-, β-, and γ-ENaC subunits, and reduced the amount of αβγ-ENaC subunits in the apical plasma membrane. Silencing HIF-2α partially prevented impaired fluid reabsorption in hypoxic rats and prevented the hypoxia-induced decrease in α- but not the βγ-subunits of ENaC protein expression resulting in a less active form of ENaC in hypoxic AEC. Inhibition of alveolar reabsorption also caused pulmonary vasoconstriction in ventilated rats. These results indicate that a HIF-2α-dependent decrease in Na(+)-transport in hypoxic alveolar epithelium decreases alveolar reabsorption. Because susceptibles to high-altitude pulmonary edema (HAPE) have decreased Na(+)-transport even in normoxia, inhibition of alveolar reabsorption by hypoxia at high altitude might further impair alveolar gas exchange. Thus, aggravated hypoxemia might further enhance hypoxic pulmonary vasoconstriction and might subsequently cause HAPE.