Journal
CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION
Volume 13, Issue 5, Pages 541-548Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00041552-200409000-00010
Keywords
aldosterone; channel-activating protease; connecting tubule; ENaC; furin
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Funding
- NHLBI NIH HHS [HL71664] Funding Source: Medline
- NIDDK NIH HHS [DK54348] Funding Source: Medline
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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 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. 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.
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