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ENaC inhibits rat lung fluid absorption in vivo
1 Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA
* To whom correspondence should be addressed. E-mail: hgfolkes{at}neoucom.edu.
We used siRNA against the 
ENaC (epithelial Na Channel) subunit to investigate ENaC involvement in lung fluid absorption in rats by the impermeable tracer technique during baseline and after 
-adrenoceptor-stimulation by terbutaline. Terbutaline-stimulation of lung fluid absorption increased fluid absorption by 165% in pSi-0-pretreated rat lungs (irrelevant siRNA-generating plasmid). Terbutaline failed to increase lung fluid absorption in rats given the specific ENaC siRNA-generating plasmid (pSi-4). pSi-4-pretreatment reduced baseline lung fluid absorption by ~30%. ENaC was undetectable in pSi-4-pretreated lungs, irrespectively of condition, while being normal in pSi-0-pretreated lungs. We carried out a dose-response analysis where the rats were given 0-200 µg/kg body wt pSi-4 and ENaC mRNA and protein expressions were analyzed. To reach 50% inhibition (IC50) for ENaC mRNA expression, 32 µg/kg body wt pSi-4 was needed and to reach IC50 for ENaC protein expression, 59 µg/kg body wt pSi-4 was needed. We tested for lung tissue specificity and found no changes in ENaC expression, either at mRNA or protein level, as well as no changes in 1-Na,K ATPase protein expression. We isolated alveolar epithelial type II cells 24 h after in vivo pSi-4 pretreatment. In these cells, ENaC mRNA was undetectable, demonstrating that alveolar epithelial ENaC expression was attenuated after intratracheal ENaC siRNA-generating plasmid DNA instillation. We tested for organ specificity and found no changes in kidney ENaC and ENaC mRNA and protein expression. Thus, we provide conclusive evidence that -adrenoceptor stimulation of lung fluid absorption is critically ENaC-dependent, while baseline lung fluid absorption seemed less ENaC-dependent.
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