Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation

Oct 8, 2019American journal of physiology. Renal physiology

Activation of stress hormone receptors increases salt transporter activity and affects its daily phosphorylation cycle

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Abstract

Acute administration of corticosterone to male C57BL6 mice doubled NCC phosphorylation without affecting total NCC abundance.

NCC phosphorylation is influenced by glucocorticoids and has a diurnal rhythm.
Disturbances in NCC phosphorylation rhythms may lead to 'nondipping' blood pressure, which is linked to increased cardiovascular risk.
Chronic blockade of the glucocorticoid receptor prevented corticosterone-induced NCC phosphorylation and activation of clock genes.
Mineralocorticoid receptor activation maintains the NCC protein pool, while glucocorticoid receptor activation regulates NCC phosphorylation.
Chronic glucocorticoid receptor blockade blunted the diurnal rhythm of NCC phosphorylation, suggesting its role in circadian blood pressure regulation.

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The sodium-chloride cotransporter (NCC) in the distal convoluted tubule contributes importantly to sodium balance and blood pressure (BP) regulation. NCC phosphorylation determines transport activity and has a diurnal rhythm influenced by glucocorticoids. Disturbing this rhythm induces "nondipping" BP, an abnormality that increases cardiovascular risk. The receptor through which glucocorticoids regulate NCC is not known. In this study, we found that acute administration of corticosterone to male C57BL6 mice doubled NCC phosphorylation without affecting total NCC abundance in both adrenalectomized and adrenal-intact mice. Corticosterone also increased the whole kidney expression of canonical clock genes: period circadian protein homolog 1 (),, cryptochrome 1, and aryl hydrocarbon receptor nuclear translocator-like protein 1. In adrenal-intact mice, chronic blockade of glucocorticoid receptor (GR) with RU486 did not change total NCC but prevented corticosterone-induced NCC phosphorylation and activation of clock genes. Blockade of mineralocorticoid receptor (MR) with spironolactone reduced the total pool of NCC but did not affect stimulation by corticosterone. The diurnal rhythm of NCC phosphorylation, measured at 6-h intervals, was blunted by chronic GR blockade, and a similar dampening of diurnal variation was seen in GR heterozygous null mice. These effects on NCC phosphorylation did not reflect altered rhythmicity of plasma corticosterone or serum and glucocorticoid-induced kinase 1 activity. Both mineralocorticoids and glucocorticoids emerge as regulators of NCC, acting via distinct receptor pathways. MR activation provides maintenance of the NCC protein pool; GR activation dynamically regulates NCC phosphorylation and establishes the diurnal rhythm of NCC activity. This study has implications for circadian BP homeostasis, particularly in individuals with abnormal glucocorticoid signaling as is found in chronic stress and corticosteroid therapy. Per1Per2

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Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation

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