Journal article
New insights into epithelial sodium channel function in the kidney: site of action, regulation by ubiquitin ligases, serum- and glucocorticoid-inducible kinase and proteolysis
Current opinion in nephrology and hypertension, Vol.13(5), pp.541-548
09/2004
DOI: 10.1097/00041552-200409000-00010
PMID: 15300161
Abstract
The epithelial sodium channel (ENaC) sets the rate of Na+ reabsorption in the collecting duct. This review describes recent advances in our understanding of ENaC function.
First, collecting duct-specific deletion of alphaENaC does not cause Na wasting in mice, suggesting that other regions can compensate. Second, Nedd4 and Nedd4-2 are ubiquitin ligases that reduce surface expression of ENaC and inhibit Na+ transport. Nedd4-2, but not Nedd4, is negatively regulated by serum- and glucocorticoid-inducible kinase 1, an aldosterone-induced kinase, providing an attractive mechanism for the stimulatory effect of aldosterone on Na+ transport. However, mice with germline ablation of serum- and glucocorticoid-inducible kinase 1 show only modest hypotension and are able to decrease Na+ excretion rates substantially. Third, maturation of ENaC is associated with processing at consensus furin cleavage sites and this cleavage is critical for channel activity. A separate class of serine proteases, the channel-activating proteases, also stimulates ENaC activity.
The connecting tubule of the kidney has abundant ENaC and Na(+)- and K(+)-transport capacity and may provide much of ENaC-mediated Na+ transport in the kidney. Aldosterone may increase Na transport, in part, by serum- and glucocorticoid-inducible kinase 1-mediated inhibition of Nedd4-2 but this has not been demonstrated in the native collecting duct or connecting tubule. The mild phenotype of the serum- and glucocorticoid-inducible kinase 1-knockout mouse points to serum- and glucocorticoid-inducible kinase 1-independent mechanisms that regulate Na+ transport. Two separate classes of protease appear to regulate Na+ transport: one is furin or furin-like and cleaves ENaC subunits to stimulate transport; the other, the channel-activating proteases, may act on ENaC or a regulatory molecule.
Details
- Title: Subtitle
- New insights into epithelial sodium channel function in the kidney: site of action, regulation by ubiquitin ligases, serum- and glucocorticoid-inducible kinase and proteolysis
- Creators
- Christie P Thomas - Department of Internal Medicine and the Graduate Program in Molecular Biology, University of Iowa College of Medicine, Iowa City, IA 52242, USA. christie-thomas@uiowa.eduOmar A Itani
- Resource Type
- Journal article
- Publication Details
- Current opinion in nephrology and hypertension, Vol.13(5), pp.541-548
- Publisher
- England
- DOI
- 10.1097/00041552-200409000-00010
- PMID
- 15300161
- ISSN
- 1062-4821
- eISSN
- 1473-6543
- Grant note
- HL71664 / NHLBI NIH HHS DK54348 / NIDDK NIH HHS
- Language
- English
- Date published
- 09/2004
- Academic Unit
- Stead Family Department of Pediatrics; Obstetrics and Gynecology; Internal Medicine
- Record Identifier
- 9983986083102771
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