Glucocorticoids and the diurnal rhythm of NCC phosphorylation: implications for blood pressure control
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Date
02/07/2016Author
Ivy, Jessica Ruth
Metadata
Abstract
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.