Mice Lacking the Circadian Clock Protein Per1 are Hypotensive

Abstract

Increasing evidence suggests that the circadian clock regulates renal function and blood pressure, but the molecular mechanisms responsible are poorly understood. The circadian clock protein Per1 regulates expression of the epithelial sodium channel (ENaC) α subunit, suggesting that the clock may affect renal Na reabsorption, and hence, blood pressure. Direct evidence in support of this hypothesis was obtained by the novel finding that Per1 knockout (KO) mice are hypotensive. Unrestrained mice were maintained on normal light-dark and dietary conditions. Per1 KO mice exhibited a 24 hr mean arterial pressure 18 mm Hg less than control mice. The Per1 KO mice had significantly lower systolic and diastolic pressures, but no differences in heart rate or activity were observed. Consistent with positive regulation of Na reabsorption by the circadian clock, identification of novel Per1 targets in renal cortical collecting duct cells demonstrated that Per1 coordinately regulated genes whose products are known to modulate ENaC or Na, K ATPase activity. Together these data suggest an essential role for the circadian clock in the maintenance of blood pressure. Supported by NIDDK, AHA.