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Respiratory distress and perinatal lethality in Nedd4-2-deficient mice

Author

Listed:
  • Natasha A. Boase

    (Centre for Cancer Biology, SA Pathology, PO Box 14, Rundle Mall)

  • Grigori Y. Rychkov

    (School of Medical Sciences, University of Adelaide)

  • Scott L. Townley

    (Centre for Cancer Biology, SA Pathology, PO Box 14, Rundle Mall)

  • Anuwat Dinudom

    (School of Medical Science, Faculty of Medicine, University of Sydney)

  • Eleanora Candi

    (Biochemistry Laboratory, University of Rome 'Tor Vergata', via Montpellier 1)

  • Anne K. Voss

    (Divsion of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Tatiana Tsoutsman

    (Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney)

  • Chris Semsarian

    (Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney)

  • Gerry Melino

    (Biochemistry Laboratory, University of Rome 'Tor Vergata', via Montpellier 1
    MRC Toxicology Unit, University of Leicester)

  • Frank Koentgen

    (Ozgene Pty Ltd, PO Box 1128)

  • David I. Cook

    (School of Medical Science, Faculty of Medicine, University of Sydney)

  • Sharad Kumar

    (Centre for Cancer Biology, SA Pathology, PO Box 14, Rundle Mall
    University of Adelaide
    School of Molecular and Biomedical Science, University of Adelaide)

Abstract

The epithelial sodium channel (ENaC) is essential for sodium homoeostasis in many epithelia. ENaC activity is required for lung fluid clearance in newborn animals and for maintenance of blood volume and blood pressure in adults. In vitro studies show that the ubiquitin ligase Nedd4-2 ubiquitinates ENaC to regulate its cell surface expression. Here we show that knockout of Nedd4-2 in mice leads to increased ENaC expression and activity in embryonic lung. This increased ENaC activity is the likely reason for premature fetal lung fluid clearance in Nedd4-2−/− animals, resulting in a failure to inflate lungs and perinatal lethality. A small percentage of Nedd4-2−/− animals survive up to 22 days, and these animals also show increased ENaC expression and develop lethal sterile inflammation of the lung. Thus, we provide critical in vivo evidence that Nedd4-2 is essential for correct regulation of ENaC expression, fetal and postnatal lung function and animal survival.

Suggested Citation

  • Natasha A. Boase & Grigori Y. Rychkov & Scott L. Townley & Anuwat Dinudom & Eleanora Candi & Anne K. Voss & Tatiana Tsoutsman & Chris Semsarian & Gerry Melino & Frank Koentgen & David I. Cook & Sharad, 2011. "Respiratory distress and perinatal lethality in Nedd4-2-deficient mice," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1284
    DOI: 10.1038/ncomms1284
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