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

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 and Sharad Kumar ()
Additional contact information
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
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
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

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1284

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