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Title: Glucocorticoids and the diurnal rhythm of NCC phosphorylation : implications for blood pressure control
Author: Ivy, Jessica Ruth
ISNI:       0000 0004 6351 800X
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2016
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Reabsorbing ~7% of the sodium load, the distal convoluted tubule plays key roles in blood pressure (BP) homeostasis. Here, Na-Cl co-transport (NCC) is the major route for apical Na entry making thiazide diuretics (NCC inhibitors) a mainstay hypertension treatment. Predictive adaptations of sodium excretory rhythms are supported by an intrinsic renal clock, which regulates transporter activity according to physiological need. Peripheral clocks can be influenced by glucocorticoids, which also have a circadian rhythm. We therefore hypothesized that NCC’s diurnal rhythm is regulated by glucocorticoids. C57BL6 mice were kept on a 12h light cycle with subjective day starting at 7am. Urine was collected in 12h periods and kidneys harvested at 1am (night) and 1pm (day). Slc12a3 (NCC encoding gene) mRNA and NCC protein abundance were similar between day and night but NCC phosphorylation at threonine 53 was significantly higher at night compared to day. Plasma and urinary corticosterone levels were elevated at night. Glucocorticoid inducible leucine zipper (GILZ) and serum and glucocorticoid inducible kinase (SGK1) transcripts also increased at night. Chronic corticosterone infusion flattened the plasma corticosterone rhythm within an intermediate physiological range. The diurnal rhythm of pT53 NCC was dampened in these mice but not in vehicle-treated mice. Blood pressure was monitored in the mice by radiotelemetry. After 2 weeks of baseline measurements mice received chronic corticosterone or vehicle for 3weeks, during the last 10 days of which they received ~80 mg/kg hydrochlorothiazide in their drinking water. At night systolic BP (SBP) was unaffected by any treatment whereas during the day SBP significantly increased following corticosterone but was unaffected by vehicle. Cosinor analysis of SBP in corticosterone and vehicle treated mice showed a marked reduction in rhythmicity, increased MESOR and reduced amplitude. In animals receiving corticosterone HCTZ partially rescued daytime SBP. This manoeuvre also improved SBP rhythmicity, reduced MESOR and increased amplitude. These data indicate that NCC phosphorylation has a diurnal rhythm that is in part regulated by glucocorticoids. They also show that alteration of the glucocorticoid rhythm affects the blood pressure rhythm in part through its effect on NCC phosphorylation. These findings may be clinically relevant in the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels such as metabolic syndrome and chronic stress.
Supervisor: Bailey, Matthew ; Flatman, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: circadian rhythm ; renal ; hypertension ; cardiovascular disease