New insights into epithelial sodium channel function in the kidney: Site of action, regulation by ubiquitin ligases, serum- and glucocorticoid-inducible kinase and proteolysis

Christie P. Thomas, Omar A. Itani

Research output: Contribution to journalReview article

41 Scopus citations

Abstract

Purpose of review: 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. Recent findings: First, collecting duct-specific deletion of αENaC 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. Summary: 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.

Original languageEnglish
Pages (from-to)541-548
Number of pages8
JournalCurrent Opinion in Nephrology and Hypertension
Volume13
Issue number5
DOIs
StatePublished - Sep 1 2004
Externally publishedYes

Keywords

  • Aldosterone
  • Channel-activating protease
  • Connecting tubule
  • ENaC
  • Furin

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