Regulation of plasma aldosterone levels and renal sodium handling by the circadian clock protein Per1

Abstract

Regulation of sodium balance by the kidney is an important determinant of long term blood pressure (BP) control. We have previously shown that the circadian clock protein Per1 regulates expression of the alpha subunit of the renal epithelial sodium channel (αENaC). Together with our recent finding that Per1 knockout (KO) mice exhibit dramatically lower BP than wild type (WT) mice, these data led to the hypothesis that the BP phenotype involves a renal Na handling mechanism. Consistent with our hypothesis, metabolic balance studies showed that Per1 KO mice excreted more urinary Na compared to WT mice. We measured plasma aldosterone (Aldo) levels in WT and Per1 KO mice at noon and midnight. WT mice experienced the expected circadian surge in Aldo. Importantly, the circadian Aldo surge did not occur and Aldo levels were significantly lower in Per1 KO mice. Thus we examined the expression of the circadian target gene Hsd3b6, an adrenal glomerulosa cell‐specific enzyme in the Aldo synthesis pathway. Whereas Hsd3b6 was expressed in a circadian manner in WT mice, that pattern was lost in Per1 KO mice. Hsd3b6 expression was significantly less in Per1 KO mice, providing one possible explanation for the lower plasma Aldo levels observed in Per1 KO mice. Taken together, these data support the hypothesis that the BP phenotype observed in mice lacking Per1 may involve a primary adrenal defect in addition to a renal defect in Na conservation.