Epigenetics and the control of the collecting duct epithelial sodium channel.

ABSTRACT: The apical membrane epithelial Na(+) channel subunit (ENaC) in series with the basolateral Na(+)/K(+)-adenosine triphosphatase mediates collecting duct Na(+) reabsorption. Aldosterone induces ?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 ?ENaC, epigenetic controls of basal and aldosterone-induced transcription of ?ENaC in the collecting duct recently were described. These epigenetic pathways involve dynamic nuclear repressor complexes targeted to specific subregions of the ?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 Sirt1, 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 Dot1a, maintain chromatin associated with the ?ENaC promoter in a stable hypermethylated state, constraining ?ENaC transcription under basal conditions. Aldosterone and serum- and glucocorticoid-induced kinase-1, itself, activate ?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 Dot1a pathways in renal salt excretion and hypertension.

SUBMITTER: Kone BC 

PROVIDER: S-EPMC3767935 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature