A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na⁺ retention

Oct 25, 2013American journal of physiology. Renal physiology

The circadian protein Per1 may help control aldosterone levels and kidney salt retention

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Abstract

Mice with reduced levels of the circadian protein Per1 exhibited decreased plasma aldosterone levels and increased urinary Na(+) excretion.

The circadian protein Per1 is linked to the expression of the enzyme 3β-dehydrogenase isomerase (3β-HSD), which is important for aldosterone production.
Knockout of Per1 in mice resulted in significantly lower blood pressure compared to wild-type mice.
In vitro studies indicate that Per1 regulates the expression of 3β-HSD in human adrenal cells.
Reduced Per1 levels in mice were associated with lower plasma aldosterone concentrations.
Metabolic cage experiments showed that Per1 heterozygotes excreted more sodium in urine than wild-type mice.

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The circadian clock plays an important role in the regulation of physiological processes, including renal function and blood pressure. We have previously shown that the circadian protein period (Per)1 regulates the expression of multiple Na(+) transport genes in the collecting duct, including the α-subunit of the renal epithelial Na(+) channel. Consistent with this finding, Per1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. We have also recently demonstrated the potential opposing actions of cryptochrome (Cry)2 on Per1 target genes. Recent work by others has demonstrated that Cry1/2 regulates aldosterone production through increased expression of the adrenal gland-specific rate-limiting enzyme 3β-dehydrogenase isomerase (3β-HSD). Therefore, we tested the hypothesis that Per1 plays a role in the regulation of aldosterone levels and renal Na(+) retention. Using RNA silencing and pharmacological blockade of Per1 nuclear entry in the NCI-H295R human adrenal cell line, we showed that Per1 regulates 3β-HSD expression in vitro. These results were confirmed in vivo: mice with reduced levels of Per1 had decreased levels of plasma aldosterone and decreased mRNA expression of 3β-HSD. We postulated that mice with reduced Per1 would have a renal Na(+)-retaining defect. Indeed, metabolic cage experiments demonstrated that Per1 heterozygotes excreted more urinary Na(+) compared with wild-type mice. Taken together, these data support the hypothesis that Per1 regulates aldosterone levels and that Per1 plays an integral role in the regulation of Na(+) retention.

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A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na⁺ retention

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