Renal Na-handling defect associated with PER1-dependent nondipping hypertension in male mice

Jan 24, 2018American journal of physiology. Renal physiology

Kidney salt handling problems linked to PER1-related nighttime high blood pressure in male mice

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Abstract

The night/day ratio of urinary sodium excretion in Per1 knockout mice is decreased compared with wild-type mice (4 × vs. 7×, P < 0.001).

Circadian rhythms influence various physiological functions, including blood pressure, which typically dips 10-20% during the night.
Patients who do not experience this nighttime dip in blood pressure are referred to as 'nondippers' and face a higher risk of cardiovascular disease.
Mice lacking the circadian clock gene Per1 develop nondipping hypertension when subjected to a high-salt diet and mineralocorticoid treatment.
Inappropriate regulation of sodium transport genes occurs in the kidneys of Per1 knockout mice under high-salt conditions.
The findings indicate that PER1 may play a role in regulating circadian blood pressure rhythms through its impact on sodium handling in the kidneys.

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Many physiological functions have a circadian rhythm, including blood pressure (BP). BP is highest during the active phase, whereas during the rest period, BP dips 10-20%. Patients that do not experience this dip at night are termed "nondippers." Nondipping hypertension is associated with increased risk of cardiovascular disease. The mechanisms underlying nondipping hypertension are not understood. Without the circadian clock gene Per1, C57BL/6J mice develop nondipping hypertension on a high-salt diet plus mineralocorticoid treatment (HS/DOCP). Our laboratory has shown that PER1 regulates expression of several genes related to sodium (Na) transport in the kidney, including epithelial Na channel (ENaC) and Na chloride cotransporter (NCC). Urinary Na excretion also demonstrates a circadian pattern with a peak during active periods. We hypothesized that PER1 contributes to circadian regulation of BP via a renal Na-handling-dependent mechanism. Na-handling genes from the distal nephron were inappropriately regulated in KO mice on HS/DOCP. Additionally, the night/day ratio of Na urinary excretion by Per1 KO mice is decreased compared with WT (4 × vs. 7×, P < 0.001, n = 6 per group). Distal nephron-specific Per1 KO mice also show an inappropriate increase in expression of Na transporter genes αENaC and NCC. These results support the hypothesis that PER1 mediates control of circadian BP rhythms via the regulation of distal nephron Na transport genes. These findings have implications for the understanding of the etiology of nondipping hypertension and the subsequent development of novel therapies for this dangerous pathophysiological condition.

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Renal Na-handling defect associated with PER1-dependent nondipping hypertension in male mice

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