Abstract
Blood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk. Hydrochlorothiazide restores the dipping BP profile in nondipping patients, suggesting that the NaCl cotransporter, NCC, is an important determinant of daily BP variation. NCC activity in cells is regulated by the circadian transcription factor per1. In vivo, circadian genes are entrained via the hypothalamic-pituitary-adrenal axis. Here, we test whether abnormalities in the day:night variation of circulating glucocorticoid influence NCC activity and BP control. C57BL6/J mice were culled at the peak (1:00 AM) and trough (1:00 PM) of BP. We found no day:night variation in NCC mRNA or protein but NCC phosphorylation on threonine(53) (pNCC), required for NCC activation, was higher when mice were awake, as was excretion of NCC in urinary exosomes. Peak NCC activity correlated with peak expression of per2 and bmal1 (clock genes) and sgk1 and tsc22d3 (glucocorticoid-responsive kinases). Adrenalectomy reduced NCC abundance and blunted the daily variation in pNCC levels without affecting variation in clock gene transcription. Chronic corticosterone infusion increased bmal1, per1, sgk1, and tsc22d3 expression during the inactive phase. Inactive phase pNCC was also elevated by corticosterone, and a nondipping BP profile was induced. Hydrochlorothiazide restored rhythmicity of BP in corticosterone-treated mice without affecting BP in controls. Glucocorticoids influence the day:night variation in NCC activity via kinases that control phosphorylation. Abnormal glucocorticoid rhythms impair NCC and induce nondipping. Night-time dosing of thiazides may be particularly beneficial in patients with modest glucocorticoid excess.
Highlights
Blood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk
Using the complementary approaches of adrenalectomy and chronic corticosterone infusion, we found that flattening the day:night variation in hypothalamic–pituitary–adrenal axis activity flattened the variation in NaCl cotransporter (NCC) activity, inducing a nondipping BP, which could be restored by thiazide therapy
BP and heart rate had a robust 24-hour rhythm, dipping during subjective day when mice were in the inactive phase (Figure S2)
Summary
Blood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk. Phosphorylation at conserved residues in the N terminus, and thereby influence NCC activity and trafficking into the apical membrane.[18] The distal tubule expresses the canonical circadian transcription factors per1/2, bmal[1], clock, and cry1/2,19 and a recent cell-line study demonstrated transcriptional regulation of NCC and WNK kinases by per1.20 It is increasingly evident that circadian transcription factors influence renal function.[21] Glucocorticoids play an important role in the entrainment of renal clocks to the day:night cycle.[22] In the aldosterone-sensitive distal nephron, glucocorticoid actions are normally limited because of metabolism by 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2).[23] modest glucocorticoid excess promotes sodium retention by activating transport in the aldosterone-sensitive distal nephron.[24] Such perturbations, whether iatrogenic[25] or because of conditions such as Cushing syndrome,[26] impair BP rhythmicity and induce a nondipping BP profile
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
