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PMID:18524855

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Citation

Shi, PP, Cao, XR, Sweezer, EM, Kinney, TS, Williams, NR, Husted, RF, Nair, R, Weiss, RM, Williamson, RA, Sigmund, CD, Snyder, PM, Staub, O, Stokes, JB and Yang, B (2008) Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2. Am. J. Physiol. Renal Physiol. 295:F462-70

Abstract

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.

Links

PubMed PMC2519178 Online version:10.1152/ajprenal.90300.2008

Keywords

Animals; Blood Pressure/drug effects; Blood Pressure/physiology; Cardiomegaly/genetics; Cardiomegaly/metabolism; Disease Models, Animal; Endosomal Sorting Complexes Required for Transport; Epithelial Sodium Channel/metabolism; Hypertension/genetics; Hypertension/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Sodium Chloride, Dietary/pharmacology; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NED4L

acts_upstream_of_or_within

GO:0010766: negative regulation of sodium ion transport

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3846431

P

  • regulates_o_occurs_in:(EMAPA:17896)

Seeded From UniProt

complete

MOUSE:NED4L

acts_upstream_of_or_within

GO:0010766: negative regulation of sodium ion transport

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3846431

P

regulates_o_occurs_in:(EMAPA:17896)

Seeded From UniProt

complete

MOUSE:NED4L

acts_upstream_of_or_within

GO:0009651: response to salt stress

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3846431

P

Seeded From UniProt

complete

MOUSE:NED4L

acts_upstream_of_or_within

GO:0003085: negative regulation of systemic arterial blood pressure

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3846431

P

Seeded From UniProt

complete


See also

References

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