The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice

Gumz, Michelle L.; Stow, Lisa R.; Lynch, I. Jeanette; Greenlee, Megan M.; Rudin, Alicia; Cain, Brian D.; Weaver, David R.; Wingo, Charles S.

doi:10.1172/jci36908

Cited by 193 publications

(198 citation statements)

References 51 publications

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“…To corroborate these findings, siRNA gene silencing was used to specifically knock down MR or GR expression. Independent transfections of MR-siRNA or GRsiRNA resulted in nearly 90% knockdown of their relevant receptor mRNAs in mIMCD-3 cells (80). In the presence of aldosterone, transfection of MR-siRNA or GR-siRNA inhibited the induction of edn1 mRNA by 35 Ϯ 8% and 40 Ϯ 4%, respectively (Fig.…”

Section: Aldosterone Stimulates Et-1 Inmentioning

confidence: 82%

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

Stow

Gumz

Lynch

et al. 2009

Journal of Biological Chemistry

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Aldosterone and endothelin-1 (ET-1) act on collecting duct cells of the kidney and are important regulators of renal sodium transport and cardiovascular physiology. We recently identified the ET-1 gene (edn1) as a novel aldosterone-induced transcript. However, aldosterone action on edn1 has not been characterized at the present time. In this report, we show that aldosterone stimulated edn1 mRNA in acutely isolated rat inner medullary collecting duct cells ex vivo and ET-1 peptide in rat inner medulla in vivo. Aldosterone induction of edn1 mRNA occurred in cortical, outer medullary, and inner medullary collecting duct cells in vitro. Inspection of the edn1 promoter revealed two putative hormone response elements. Levels of heterogeneous nuclear RNA synthesis demonstrated that edn1 mRNA stimulation occurred at the level of transcription. RNA knockdowns corroborated pharmacological studies and demonstrated both mineralocorticoid receptor and glucocorticoid receptor participated in this response. Aldosterone resulted in dose-dependent nuclear translocation and binding of mineralocorticoid receptor and glucocorticoid receptor to the edn1 hormone response elements. Hormone receptors mediated the association of chromatin remodeling complexes, histone modification, and RNA polymerase II at the edn1 promoter. Direct interaction between aldosterone and ET-1 has important implications for renal and cardiovascular function.The steroid hormone aldosterone is critical for sodium homeostasis and blood pressure control. Aldosterone works by modulating the fine regulation of sodium reabsorption in the distal nephron and collecting duct of the kidney. Classic aldosterone action is mediated through the mineralocorticoid receptor (MR), 3 a member of the nuclear receptor family of proteins that function as ligand-dependent transcription factors (1). MR acts on cells of the distal nephron and collecting duct to stimulate transcription of genes involved in transepithelial sodium transport, including the epithelial sodium channel ␣ subunit (scnn1a, ␣ENaC), the sodium, potassium-ATPase ␣1 subunit (atp1a1), and the serum-and glucocorticoid-regulated kinase-1 (sgk1) (2). The increase in expression of genes involved in sodium transport results in net sodium reabsorption followed by in increase in extracellular fluid volume and a consequent increase in blood pressure. Indeed, MR antagonists such as spironolactone and eplerenone are used clinically as diuretic and anti-hypertensive agents (3). The mechanism of MR action is consistent with a classic steroid receptor mechanism (4). Prior to activation MR resides in the cytosol. Ligand binding induces a conformational change that releases chaperone proteins and reveals a nuclear localization signal. Nuclear MR binds directly to DNA at hormone response elements (HREs) in target genes to modulate their transcription. A typical HRE for MR consists of two receptor binding half-sites with the consensus sequence 5Ј-TGTTCT-3Ј, arranged as an inverted palindrome (1, 5). These HREs facilitate binding of...

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Section: Aldosterone Stimulates Et-1 Inmentioning

confidence: 82%

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

Stow

Gumz

Lynch

et al. 2009

Journal of Biological Chemistry

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“…8,9 Although the BP phenotype of Period Ϫ/Ϫ mice has not been reported, these mice fed the standard diet also had higher Na ϩ excretion and lower ␣ENaC expression than WT controls. 20 Another feature not limited to Af17 Ϫ/Ϫ mice is that the changes in Na ϩ reabsorption are not accompanied by an inverse effect on K ϩ , indicating that the impaired ENaC function can not account for the complete panoply of the renal dysfunction. Indeed, such coupling was not observed in Sgk1 Ϫ/Ϫ , 17,37 AS Ϫ/Ϫ , 13 ␣ENaC( Ϫ/Ϫ )Tg, 38 and ␤ENaC m/m mice.…”

Section: High Dietary Potassium Attenuated the Effect Of Af17mentioning

confidence: 99%

“…To date, a direct link between a particular gene impinging histone modifications to BP has not been clearly established. Second, numerous mouse models lacking ENaC and their direct or indirect regulators such as AS, 13 angiotensinogen (Agt), 14 angiotensin-converting enzyme (ACE), 15 MR, 16 Sgk1, 17 WNK1, 18 WNK4, 19 and Period 20 have been reported. However, the role of these models in showing the epigenetic control of BP is still unclear.…”

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confidence: 99%

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Chen¹,

H²,

Pochynyuk

et al. 2011

Journal of the American Society of Nephrology

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The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP.

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“…7 Our subsequent reports showed that Per1 regulates the expression of the a subunit of the epithelial sodium channel and the activity of epithelial sodium channel. 8,9 Consistent with these mechanistic molecular findings in renal models, studies in circadian KO mice have consistently demonstrated a role for each of the core clock proteins in BP control. [10][11][12][13] An important role for the kidney in these BP phenotypes has often been proposed, but the lack of renal cell type-specific KO models of circadian genes has prevented the use of a genetic model to directly test this hypothesis.…”

mentioning

confidence: 62%

“…8,13,15 The features of these phenotypes include reduced plasma aldosterone, mild polyuria, altered urinary sodium excretion, and reduced BP. These shared features between global loss of CLOCK or Per1 and a kidneyspecific Bmal1 KO are consistent with the notion that the kidney significantly contributes to the phenotypes observed in the global KO mice.…”

mentioning

confidence: 99%