Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2.
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.
Shi
Peijun P
PP
Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, USA.
Cao
Xiao R
XR
Sweezer
Eileen M
EM
Kinney
Thomas S
TS
Williams
Nathan R
NR
Husted
Russell F
RF
Nair
Ramesh
R
Weiss
Robert M
RM
Williamson
Roger A
RA
Sigmund
Curt D
CD
Snyder
Peter M
PM
Staub
Olivier
O
Stokes
John B
JB
Yang
Baoli
B
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017673:Sodium Chloride, Dietary; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases