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This Article Full Text Full Text (PDF) Supplemental Video and Other Materialss All Versions of this Article: 295/2/F462    most recent 90300.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shi, P. P. Articles by Yang, B. PubMed PubMed Citation Articles by Shi, P. P. Articles by Yang, B.

Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2

Departments of ¹Obstetrics and Gynecology, ²Internal Medicine, and ³Pathology, Carver College of Medicine, University of Iowa, Iowa City; ⁴Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; and ⁵Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 9 May 2008 ; accepted in final form 3 June 2008

Nedd4-2 has been proposed to play a critical role in regulating epithelial Na⁺ channel (ENaC) activity. Biochemical and overexpression experiments suggest that Nedd4-2 binds to the PY motifs of ENaC subunits via its WW domains, ubiquitinates them, and decreases their expression on the apical membrane. Phosphorylation of Nedd4-2 (for example by Sgk1) may regulate its binding to ENaC, and thus ENaC ubiquitination. These results suggest that the interaction between Nedd4-2 and ENaC may play a crucial role in Na⁺ homeostasis and blood pressure (BP) regulation. To test these predictions in vivo, we generated Nedd4-2 null mice. The knockout mice had higher BP on a normal diet and a further increase in BP when on a high-salt diet. The hypertension was probably mediated by ENaC overactivity because 1) Nedd4-2 null mice had higher expression levels of all three ENaC subunits in kidney, but not of other Na⁺ transporters; 2) the downregulation of ENaC function in colon was impaired; and 3) NaCl-sensitive hypertension was substantially reduced in the presence of amiloride, a specific inhibitor of ENaC. Nedd4-2 null mice on a chronic high-salt diet showed cardiac hypertrophy and markedly depressed cardiac function. Overall, our results demonstrate that in vivo Nedd4-2 is a critical regulator of ENaC activity and BP. The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder.

ion channels; kidney; sodium channels