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Oxygen and Glucocorticoids Modulate ENaC mRNA Translation in Fetal Distal Lung Epithelium

CIHR Group in Lung Development, Programme in Lung Biology Research, Hospital for Sick Children Research Institute, and Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Gail Otulakowski, Ph.D., Programme in Lung Biology Research, Hospital for Sick Children Research Institute, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: gail.otulakowski{at}sickkids.ca

Glucocorticoid hormones play an important role in fetal lung maturation. It is unknown how they interact with changes in O₂ tension, which play an important role in converting the lung from a fluid-secreting to a fluid-absorbing organ at birth. Airspace fluid absorption arises from active transepithelial Na⁺ transport with the amiloride-sensitive epithelial Na channel (ENaC), consisting of , , and subunits, representing the rate-limiting step under nonpathologic conditions. We investigated the individual and combined effects of dexamethasone (DEX) and PO₂ on ENaC mRNA levels, rate of ENaC protein synthesis, and amiloride-sensitive short-circuit current in primary cultures of rat fetal distal lung epithelial cells. DEX significantly induced ENaC mRNA in fetal (3%) and postnatal (21%) O₂, but increases in ENaC protein synthesis and function occurred only when epithelia were grown under a postnatal PO₂. Sucrose density gradient analyses showed that DEX treatment of cells cultured at 3% O₂ decreased the association of ENaC mRNA with large polysomes and enhanced the association with small polysomes. Conversely, incubation of DEX-treated cells in 21% O₂ restored ENaC mRNA association with large polysomes. No significant changes were seen in the overall polyribosome profiles or in the distribution of mRNAs encoding and subunits of ENaC or cytokeratin 18, indicating specific modulation of ENaC mRNA translation. These data suggest that postnatal O₂ exposure may be important for efficient translation of the ENaC mRNA.

Key Words: ion transport • translational regulation • postnatal gas exchange • fluid absorption

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