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Regulation of ?ENaC transcription.

ABSTRACT: Aldosterone is a major regulator of Na(+) absorption and acts primarily by controlling the epithelial Na(+) channel (ENaC) function at multiple levels including transcription. ENaC consists of ?, ?, and ? subunits. In the classical model, aldosterone enhances transcription primarily by activating mineralocorticoid receptor (MR). However, how aldosterone induces chromatin alternation and thus leads to gene activation or repression remains largely unknown. Emerging evidence suggests that Dot1a-Af9 complex plays an important role in repression of ?ENaC by directly binding and modulating targeted histone H3 K79 hypermethylation at the specific subregions of ?ENaC promoter. Aldosterone impairs Dot1a-Af9 formation by decreasing expression of Dot1a and Af9 and by inducing Sgk1, which, in turn, phosphorylates Af9 at S435 to weaken Dot1a-Af9 interaction. MR counterbalances Dot1a-Af9 action by competing with Dot1a for binding Af9. Af17 derepresses ?ENaC by competitively interacting with Dot1a and facilitating Dot1a nuclear export. Consistently, MR(-/-) mice have impaired ENaC expression at day 5 after birth, which may contribute to progressive development of pseudohypoaldosteronism type 1 in a later stage. Af17(-/-) mice have decreased ENaC expression, renal Na(+) retention, and blood pressure. In contrast, Dot1l(AC) mice have increased ?ENaC expression, despite a 20% reduction of the principal cells. This chapter reviews these findings linking aldosterone action to ENaC transcription through chromatin modification. Future direction toward the understanding the role of Dot1a-Af9 complex beyond ENaC regulation, in particular, in renal fibrosis is also briefly discussed.

SUBMITTER: Chen L

PROVIDER: S-EPMC4867546 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Regulation of αENaC transcription.

Chen Lihe L Zhang Xi X Zhang Wenzheng W

Vitamins and hormones 20150214

Aldosterone is a major regulator of Na(+) absorption and acts primarily by controlling the epithelial Na(+) channel (ENaC) function at multiple levels including transcription. ENaC consists of α, β, and γ subunits. In the classical model, aldosterone enhances transcription primarily by activating mineralocorticoid receptor (MR). However, how aldosterone induces chromatin alternation and thus leads to gene activation or repression remains largely unknown. Emerging evidence suggests that Dot1a-Af9 ...[more]

PMID: 25817867

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Project description:Reissner's membrane epithelium forms much of the barrier that produces and sustains the large ionic differences between cochlear endolymph and perilymph. We have reported that Reissner's membrane contributes to normal cochlear function by absorbing Na(+) from endolymph via amiloride-sensitive channels in gerbil inner ear. We used mouse Reissner's membrane to 1) identify candidate genes involved in the Na(+) transport pathway, 2) determine whether their level of expression was regulated by the synthetic glucocorticoid dexamethasone, and 3) obtain functional evidence for the physiological importance of these genes. Transcripts were present for alpha-, beta-, and gamma-subunits of epithelial Na(+) channel (ENaC); corticosteroid receptors GR (glucocorticoid receptor) and MR (mineralocorticoid receptor); GR agonist regulator 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11beta-HSD1); Na(+) transport control components SGK1, Nedd4-2, and WNKs; and K(+) channels and Na(+)-K(+)-ATPase. Expression of the MR agonist regulator 11beta-HSD2 was not detected. Dexamethasone upregulated transcripts for alpha- and beta-subunits of ENaC ( approximately 6- and approximately 3-fold), KCNK1 ( approximately 3-fold), 11beta-HSD1 ( approximately 2-fold), SGK1 ( approximately 2-fold), and WNK4 ( approximately 3-fold). Transepithelial currents from the apical to the basolateral side of Reissner's membrane were sensitive to amiloride (IC(50) approximately 0.7 muM) and benzamil (IC(50) approximately 0.1 muM), but not EIPA (IC(50) approximately 34 muM); amiloride-blocked transepithelial current was not immediately changed by forskolin/IBMX. Currents were reduced by ouabain, lowered bath Na(+) concentration (from 150 to 120 mM), and K(+) channel blockers (XE-991, Ba(2+), and acidification from pH 7.4 to 6.5). Dexamethasone-stimulated current and gene expression were reduced by mifepristone, but not spironolactone. These molecular, pharmacological, and functional observations are consistent with Na(+) absorption by mouse Reissner's membrane, which is mediated by apical ENaC and/or other amiloride-sensitive channels, basolateral Na(+)-K(+)-ATPase, and K(+)-permeable channels and is under the control of glucocorticoids. These results provide an understanding and a molecular definition of an important transport function of Reissner's membrane epithelium in the homeostasis of cochlear endolymph.

Dataset Information

Regulation of ?ENaC transcription.

Publications

Regulation of αENaC transcription.

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