Shi, Peijun P.;
Cao, Xiao R.;
Sweezer, Eileen M.;
Kinney, Thomas S.;
Williams, Nathan R.;
Husted, Russell F.;
Nair, Ramesh;
Weiss, Robert M.;
Williamson, Roger A.;
Sigmund, Curt D.;
Snyder, Peter M.;
Staub, Olivier;
Stokes, John B.;
Yang, Baoli
Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2
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Media type:
E-Article
Title:
Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2
Contributor:
Shi, Peijun P.;
Cao, Xiao R.;
Sweezer, Eileen M.;
Kinney, Thomas S.;
Williams, Nathan R.;
Husted, Russell F.;
Nair, Ramesh;
Weiss, Robert M.;
Williamson, Roger A.;
Sigmund, Curt D.;
Snyder, Peter M.;
Staub, Olivier;
Stokes, John B.;
Yang, Baoli
imprint:
American Physiological Society, 2008
Published in:American Journal of Physiology-Renal Physiology
Language:
English
DOI:
10.1152/ajprenal.90300.2008
ISSN:
1931-857X;
1522-1466
Origination:
Footnote:
Description:
<jats:p> Nedd4-2 has been proposed to play a critical role in regulating epithelial Na<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> 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. </jats:p>