The Circadian Protein Period 1 Contributes to Blood Pressure Control and Coordinately Regulates Renal Sodium Transport Genes

Apr 25, 2012Hypertension (Dallas, Tex. : 1979)

The daily rhythm protein Period 1 helps control blood pressure and regulates kidney genes for sodium balance

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Abstract

Mice lacking functional Per1 exhibit significantly reduced blood pressure.

The circadian clock protein Per1 regulates the expression of the α subunit of the renal epithelial sodium channel and other sodium handling genes.
Knockdown of Per1 in collecting duct cells leads to decreased expression of the α-epithelial sodium channel and Fxyd5, a positive regulator of sodium transport.
After Per1 knockdown, the expression of caveolin 1, Ube2e3, and ET-1, which negatively affect the epithelial sodium channel, is increased.
Elevated levels of renal ET-1 are associated with the lower blood pressure observed in Per1 knockout mice.
These findings suggest that Per1 plays a role in regulating both renal sodium reabsorption and blood pressure.

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The circadian clock protein period 1 (Per1) contributes to the regulation of expression of the α subunit of the renal epithelial sodium channel at the basal level and in response to the mineralocorticoid hormone aldosterone. The goals of the present study were to define the role of Per1 in the regulation of additional renal sodium handling genes in cortical collecting duct cells and to evaluate blood pressure (BP) in mice lacking functional Per1. To determine whether Per1 regulates additional genes important in renal sodium handling, a candidate gene approach was used. Immortalized collecting duct cells were transfected with a nontarget small interfering RNA or a Per1-specific small interfering RNA. Expression of the genes for α-epithelial sodium channel and Fxyd5, a positive regulator of Na, K-ATPase activity, decreased in response to Per1 knockdown. Conversely, mRNA expression of caveolin 1, Ube2e3, and ET-1, all negative effectors of epithelial sodium channel, was induced after Per1 knockdown. These results led us to evaluate BP in Per1 KO mice. Mice lacking Per1 exhibit significantly reduced BP and elevated renal ET-1 levels compared with wild-type animals. Given the established role of renal ET-1 in epithelial sodium channel inhibition and BP control, elevated renal ET-1 is one possible explanation for the lower BP observed in Per1 KO mice. These data support a role for the circadian clock protein Per1 in the coordinate regulation of genes involved in renal sodium reabsorption. Importantly, the lower BP observed in Per1 KO mice compared with wild-type mice suggests a role for Per1 in BP control as well.

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The Circadian Protein Period 1 Contributes to Blood Pressure Control and Coordinately Regulates Renal Sodium Transport Genes

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