Journal article
Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2
American Journal of Physiology - Renal Physiology, Vol.295(2), pp.F462-F470
06/04/2008
DOI: 10.1152/ajprenal.90300.2008
PMCID: PMC2519178
PMID: 18524855
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.
Details
- Title: Subtitle
- Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2
- Creators
- Peijun P ShiXiao R CaoEileen M SweezerThomas S KinneyNathan R WilliamsRussell F HustedRamesh NairRobert M Weiss - University of Iowa, Cardiovascular MedicineRoger A Williamson - University of Iowa, Obstetrics and GynecologyCurt D Sigmund - University of Iowa, Neuroscience and PharmacologyPeter M Snyder - University of Iowa, Cardiovascular MedicineOlivier StaubJohn B StokesBaoli Yang - University of Iowa, BioVentures Center
- Resource Type
- Journal article
- Publication Details
- American Journal of Physiology - Renal Physiology, Vol.295(2), pp.F462-F470
- DOI
- 10.1152/ajprenal.90300.2008
- PMID
- 18524855
- PMCID
- PMC2519178
- NLM abbreviation
- Am J Physiol Renal Physiol
- ISSN
- 0363-6127
- eISSN
- 1522-1466
- Publisher
- American Physiological Society
- Language
- English
- Date published
- 06/04/2008
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; BioVentures Center; Obstetrics and Gynecology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Medicine Administration; Internal Medicine
- Record Identifier
- 9983557604202771
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