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The Epithelial Na⁺ Channel: Cell Surface Insertion and Retrieval in Na⁺ Homeostasis and Hypertension

Departments of Internal Medicine and Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52422

Correspondence: Address all correspondence and requests for reprints to: Peter M. Snyder, M.D., Department of Internal Medicine, University of Iowa College of Medicine, 371 EMRB, Iowa City, Iowa 52242. E-mail: psnyder{at}blue.weeg.uiowa.edu

The epithelial Na⁺ channel (ENaC) forms the pathway for Na⁺ absorption in the kidney collecting duct and other epithelia. Dominant gain-of-function mutations cause Liddle’s syndrome, an inherited form of hypertension resulting from excessive renal Na⁺ absorption. Conversely, loss-of-function mutations cause pseudohypoaldosteronism type I, a disorder of salt wasting and hypotension. Thus, ENaC has a critical role in the maintenance of Na⁺ homeostasis and blood pressure control. Altered Na⁺ absorption in the lung may also contribute to the pathogenesis of cystic fibrosis. Epithelial Na⁺ absorption is regulated in large part by mechanisms that control the expression of ENaC at the cell surface. Nedd4, a ubiquitin protein ligase, binds to ENaC and targets the channel for endocytosis and degradation. Liddle’s syndrome mutations disrupt the interaction between ENaC and Nedd4, resulting in an increase in the number of ENaC channels at the cell surface. Aldosterone and vasopressin also regulate Na⁺ absorption to defend against hypotension and hypovolemia. Both hormones increase the expression of ENaC at the cell surface. The goal of this review is to summarize recent data on the regulation of ENaC expression at the cell surface.

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