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World J Nephrol. Jul 6, 2015; 4(3): 363-366
Published online Jul 6, 2015. doi: 10.5527/wjn.v4.i3.363
Epigenetics of epithelial Na+ channel-dependent sodium uptake and blood pressure regulation
Wenzheng Zhang
Wenzheng Zhang, Graduate School of Biomedical Sciences, the University of Texas Health Science Center at Houston, Houston, TX 77030, United States
Wenzheng Zhang, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX 77030, United States
Author contributions: The author solely contributed to this paper.
Supported by National Institutes of Health Grant 2R01 DK080236 06A1.
Conflict-of-interest statement: The author has declared that no conflict of interest exists.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Wenzheng Zhang, Associate Professor, Department of Internal Medicine, University of Texas Medical School at Houston, MSB 5.135, 6431 Fannin, Houston, TX 77030, United States. wenzheng.zhang@uth.tmc.edu
Telephone: +1-713-5006862 Fax: +1-713-5006882
Received: November 1, 2014
Peer-review started: November 9, 2014
First decision: November 27, 2014
Revised: May 6, 2015
Accepted: May 16, 2015
Article in press: May 18, 2015
Published online: July 6, 2015
Processing time: 246 Days and 19.4 Hours
Abstract

The epithelial Na+ channel (ENaC) consists of α, β, γ subunits. Its expression and function are regulated by aldosterone at multiple levels including transcription. ENaC plays a key role in Na+ homeostasis and blood pressure. Mutations in ENaC subunit genes result in hypertension or hypotension, depending on the nature of the mutations. Transcription of αENaC is considered as the rate-limiting step in the formation of functional ENaC. As an aldosterone target gene, αENaC is activated upon aldosterone- mineralocorticoid receptor binding to the cis-elements in the αENaC promoter, which is packed into chromatin. However, how aldosterone alters chromatin structure to induce changes in transcription is poorly understood. Studies by others and us suggest that Dot1a-Af9 complex represses αENaC by directly binding and regulating targeted histone H3 K79 hypermethylation at the specific subregions of αENaC promoter. Aldosterone decreases Dot1a-Af9 formation by impairing expression of Dot1a and Af9 and by inducing Sgk1, which, in turn, phosphorylates Af9 at S435 to weaken Dot1a-Af9 interaction. MR attenuates Dot1a-Af9 effect by competing with Dot1a for binding Af9. Af17 relieves repression by interfering with Dot1a-Af9 interaction and promoting Dot1a nuclear export. Af17-/- mice exhibit defects in ENaC expression, renal Na+ retention, and blood pressure control. This review gives a brief summary of these novel findings.

Keywords: Gene transcription; Chromatin; Epithelial sodium channel; Histone; Blood pressure

Core tip: The epithelial Na+ channel (ENaC) is a key player in sodium transport and blood pressure control. This minireview summarizes the epigenetic mechanisms governing the transcription of αENaC. The epigenetic control involves Dot1a-Af9-mediated repression through targeted hypermethylation of histone H3 K79. Aldosterone relieves the repression by decreasing Dot1a and Af9 mRNA levels and by weakening the protein-protein interaction between Dot1a and Af9 interaction via Sgk1-catalyzed Af9 phosphorylation. Aldosterone-independent mechanism involves Af17 as a competitor of Af9 for binding Dot1a and stimulator of Dot1a nuclear export. Af17-/- mice exhibit decreased Na+ reabsorption and lowered blood pressure, indicating the significance of this epigenetic control.