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

Abstract

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 ( Per1), Per2, 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.

Chronodisruption: A Poorly Recognized Feature of CKD

“…Both mineralocorticoids and glucocorticoids regulate NCC activity. Mineralocorticoid receptor activation maintains the NCC protein pool while glucocorticoid receptor activation regulates NCC phosphorylation and the diurnal rhythm of NCC activity [43]. ATP1B1 encodes the β1 subunit of the Na + /K + -ATPase.…”

High salt intake activates the hypothalamic-pituitary-adrenal axis, amplifies the stress response, and alters tissue glucocorticoid exposure in mice

“…Certainly, synthetic glucocorticoids can induce negative sodium balance 49 , largely attributable to hemodynamic effects 50 . However, glucocorticoid receptor activation stimulates renal sodium transport 51, 52 and glucocorticoid excess typically promotes sodium retention and salt-sensitive BP abnormalities 53–55 . Moreover, high salt initially reduced circulating corticosterone.…”

Nuclear receptors in renal health and disease

“… 129 Renal GR can also activate the circadian rhythm of sodium chloride cotransporter (NCC) and prevent its phosphorylation, which has a profound impact on the diurnal dynamic balance of blood pressure. 130 Hydrocortisone can protect the kidneys and inhibit the activity of NF-κB by increasing the expression of GRα in the kidneys of rats with sepsis. 131 In addition, GR blockers were capable of restoring the renal antioxidant barrier by inhibiting the activities of adenosine deaminase and xanthine oxidase, implicating the involvements of GR in renal dysfunctions caused by combined oral contraceptive via disrupted glutathione antioxidative barrier.…”