Epigenetics and the Control of the Collecting Duct Epithelial Sodium Channel

The apical membrane epithelial Na+ channel subunit (ENaC) in series with the basolateral K+-adenosine triphosphatase mediates collecting duct Na+ reabsorption. Aldosterone induces alpha ENaC gene transcription, which appears to be rate limiting for ENaC activity in this segment. Although this response has long been assumed to be solely the result of liganded nuclear hormone receptors trans-activating alpha ENaC, epigenetic controls of basal and aldosterone-induced transcription of alpha ENaC in the collecting duct recently were described. These epigenetic pathways involve dynamic nuclear repressor complexes targeted to specific subregions of the alpha ENaC promoter and consisting of the histone methyltransferase disrupter of telomeric silencing (Dot)1a together with the transcriptional factor Af9 or the nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase Sirtl, key co-regulatory proteins, including serum- and glucocorticoid-induced kinase-1 and the putative transcription factor Af17, and targeted chromatin modifications. The complexes, through the action of Dot 1a, maintain chromatin associated with the alpha ENaC promoter in a stable hypermethylated state, constraining alpha ENaC transcription under basal conditions. Aldosterone and serum- and glucocorticoid-induced kinase-1, itself, activate alpha ENaC transcription in large part by disrupting or diminishing the Dot1a-Af9 and Dot1a-Sirt1 complexes and their effects on chromatin. Mouse models indicate potential roles of the Doti a pathways in renal salt excretion and hypertension. (C) 2013 Elsevier Inc. All rights reserved.