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Early death due to defective neonatal lung liquid clearance in αENaC-deficient mice

Abstract

The amiloride-sensitive epithelial sodium channel, ENaC, is a heteromultimeric protein made up of three homologous subunits (α, β and γ)1,2. In vitro, assembly and expression of functional active sodium channels in the Xenopus oocyte is strictly dependent on αENaC — the β and γ sub-units by themselves are unable to induce an amiloride-sensitive sodium current in this heterologous expression system2. In vivo, ENaC constitutes the limiting step for sodium absorption in epithelial cells that line the distal renal tubule, distal colon and the duct of several exocrine glands. The adult lung expresses α, β and γ ENaC3,4, and an amiloride-sensitive electrogenic sodium reabsorption has been documented in upper and lower airways3–7, but it is not established whether this sodium transport is mediated by ENaC in vivo. We inactivated the mouse αENaC gene by gene targeting. Amiloride-sensitive electrogenic Na+ transport was abolished in airway epithelia from αENaC(−/−) mice. αENaC(−/−) neonates developed respiratory distress and died within 40 h of birth from failure to clear their lungs of liquid. This study shows that ENaC plays a critical role in the adaptation of the newborn lung to air breathing.

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References

  1. Canessa, C.M., Horisberger, J.D. & Rossier, B.C. Epithelial sodium channel related to proteins involved in neurodegeneration. Nature 361, 467–470 (1993).

    Article  CAS  Google Scholar 

  2. Canessa, C.M. et al. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature. 367, 463–467 (1994).

    Article  CAS  Google Scholar 

  3. O'Brodovich, H., Canessa, C.M., Ueda, J., Rafii, B., Rossier, B.C. & Edelson, J. Expression of the epithelial Na+ Channel in the developing rat lung. Am. J Physiol 265, C491–C496 (1993).

    Article  CAS  Google Scholar 

  4. Voilley, N. et al. The lung amiloride-sensitive Na+ channel - biophysical properties, pharmacology, ontogenesis, and molecular cloning. Proc. Natn.Acad. Sci. USA 91, 247–25 (1994).

    Article  CAS  Google Scholar 

  5. O'Brodovich, H., Hannam, V., Seear, M. & Mullen, J.B.M. Amiloride impairs lung water clearance in newborn guinea pigs. J. Appl. Physiol. 68, 1758–1762 (1990).

    Article  CAS  Google Scholar 

  6. Krochmal-Mokrzan, E.M., Barker, P.M. & Gatzy, J.T. Effects of hormones on potential difference and liquid balance across explants from proximal and distal fetal rat lung. J. Physiol. 463, 647–665 (1993).

    Article  CAS  Google Scholar 

  7. Barker, P.M. & Gatzy, J.T. Effect of gas composition on liquid secretion by explants of distal lung of fetal rat in submersion culture. Am. J. Physiol. 265, L512–L517 (1993).

    CAS  PubMed  Google Scholar 

  8. Miettinen, P.J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).

    Article  CAS  Google Scholar 

  9. Cole, T.J. et al. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 9, 1608–1621 (1995).

    Article  CAS  Google Scholar 

  10. Matalon, S. et al. Fetal lung epithelial cells contain two populations of amiloride-sensitive Na+ channels. Am. J. Physiol. 264, L357–L364 (1993).

    CAS  PubMed  Google Scholar 

  11. Shimkets, R.A. et al. Liddle's syndrome: Heritable human hypertension caused by mutations in the p subunit of the epithelial sodium channel. Cell. 79, 407–414 (1994).

    Article  CAS  Google Scholar 

  12. Hansson, J.H. et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit: Genetic heterogeneity of Liddle syndrome. Nature Genet. 11, 76–82 (1995).

    Article  CAS  Google Scholar 

  13. Schild, L., Canessa, C.M., Shimkets, R.A., Gautschi, I., Lifton, R.P. & Rossier, B.C. A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. Proc. Natl. Acad. Sci. USA 92, 5699–5703 (1995).

    Article  CAS  Google Scholar 

  14. Stutts, M.J. et al. CFTR as a cAMP-dependent regulator of sodium channels. Science. 269, 847–850 (1995).

    Article  CAS  Google Scholar 

  15. Cheek, D.B. & Perry, J.W. A salt wasting syndrome in infancy. Arch. Dis. Child. 33, 252–256 (1959).

    Article  Google Scholar 

  16. Hanukoglu, A. Type 1 pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects. J. Clin. Endocr. Metab. 73, 936–944 (1991).

    Article  CAS  Google Scholar 

  17. Olver, R.E., Ramsden, C.A., Strang, L.B. & Walters, D.V. The role of amiloride-blockable sodium transport in adrenaline-induced lung liquid reabsorption in the fetal lamb. J. Physiol. 376, 321–340 (1986).

    Article  CAS  Google Scholar 

  18. Strang, L.B. Fetal lung liquid: secretion and reabsorption. Physiol. Rev. 71, 991–1016 (1991).

    Article  CAS  Google Scholar 

  19. Tchepichev, S., Ueda, J., Canessa, C.M., Rossier, B.C. & O'Brodovich, H. Lung epithelial Na channel subunits are differentially regulated during development and by steroids. Am. J. Physiol. 269, C805–C812 (1995).

    Article  CAS  Google Scholar 

  20. Wegman, M.E. Annual summary of vital statistics. Pediatrics. 92, 743–754 (1992).

    Google Scholar 

  21. Jobe, A.H. Pulmonary surfactant therapy. N. Engl. J. Med 328, 861–868 (1993).

    Article  CAS  Google Scholar 

  22. Adra, C.N., Boer, P.H. & McBurney, M.W. Cloning and expression of the mouse pgk-1 gene and the nucleotide sequence of its promoter. Gene 60, 65–74 (1987).

    Article  CAS  Google Scholar 

  23. Selfridge, J., Pow, A.M., McWhir, J., Magin, T.M. & Melton, D.W. Gene targeting using a mouse HPRT minigene/HPRT-deficient embryonic stem cell system: inactivation of the mouse ERCC-1 gene. Som. Cell Mot. Genet. 18, 325–336 (1992).

    Article  CAS  Google Scholar 

  24. Hummler, E. et al. Targeted mutation of the cAMP response element binding protein (CREB) gene: compensation within the CREB/ATF family of transcription factors Proc. Natl. Acad. Sci. USA. 91, 5647–5651 (1994).

    Article  CAS  Google Scholar 

  25. Beermann, F., Hummler, E., Schmid, E. & Schutz, G. Perinatal activation of a tyrosine aminotransferase fusion gene does not occur in albino lethal mice. Mech. Dev. 42, 49–65 (1993).

    Article  Google Scholar 

  26. Schmidt, A. & Beermann, F. Molecular basis of dark-eyed albinism in the mouse. Proc. Natl. Acad. Sci. USA 91, 4756–4760 (1994).

    Article  CAS  Google Scholar 

  27. Tso, J.Y., Sun, X.H., Kao, T.H., Reece, K.S. & Wu, R. Isolation and characterization of rat and human glyceraldehyde dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucl. Acids Res. 13, 2485–2502 (1985).

    Article  CAS  Google Scholar 

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Hummler, E., Barker, P., Gatzy, J. et al. Early death due to defective neonatal lung liquid clearance in αENaC-deficient mice. Nat Genet 12, 325–328 (1996). https://doi.org/10.1038/ng0396-325

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