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

Abstract

The circadian clock protein Period 1 (Per1) contributes to the regulation of expression of the α subunit of the renal epithelial sodium channel (αENaC) 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 BP in mice lacking functional Per1. To determine if Per1 regulates additional genes important in renal sodium handling, a candidate gene approach was employed. Immortalized collecting duct cells were transfected with a non-target siRNA or a Per1 specific siRNA. Expression of the genes for αENaC 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 ENaC, was induced following 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 to wild type animals. Given the established role of renal ET-1 in ENaC inhibition and blood pressure control, elevated renal ET-1 is one possible explanation for the lower blood pressure 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 to wild type suggests a role for Per1 in BP control as well.

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

“…Per and Cry dimerize and interact with Clock and Bmal1 to repress their transcriptional activity (3,11). Per1 may not act as a canonical repressor, however, as increasing evidence suggests that Per1 may activate gene expression through an unknown mechanism, and this may occur in a tissue-and gene-specific manner (8,16,18,31,36). However, our recent work (30) demonstrated that this possible mechanism could be through repression of the circadian repressor Cry2.…”

“…Surprisingly, no changes were observed in the expression of the aldosterone synthase gene (CYPB11), which encodes the ratelimiting step of aldosterone production. We (16,18,31,36) have previously shown that Per1 regulates both the basal and aldosterone-mediated regulation of the ␣-subunit of the renal epithelial Na ϩ channel (␣-ENaC). We (26) have also demonstrated that Per1 coordinately regulates the expression of multiple genes that contribute to the regulation of renal Na ϩ reabsorption.…”

Tick Tock

“…Similar relationships between systolic BP and a J-shaped relationship for diastolic BP have been demonstrated in patients receiving maintenance hemodialysis, as well as in patients with less advanced CKD who do not require dialysis. 12,13 In the absence of aortic valve insufficiency, the pattern of high systolic BP, low diastolic BP, and increased pulse pressure are a marker of vascular stiffness. This has been extensively studied in CKD and ESRD, and it reflects accelerated arteriosclerosis and vascular calcification in progressive renal disease.…”

“…8,9 Consistent with these mechanistic molecular findings in renal models, studies in circadian KO mice have consistently demonstrated a role for each of the core clock proteins in BP control. [10][11][12][13] An important role for the kidney in these BP phenotypes has often been proposed, but the lack of renal cell type-specific KO models of circadian genes has prevented the use of a genetic model to directly test this hypothesis.…”

“…8,13,15 The features of these phenotypes include reduced plasma aldosterone, mild polyuria, altered urinary sodium excretion, and reduced BP. These shared features between global loss of CLOCK or Per1 and a kidneyspecific Bmal1 KO are consistent with the notion that the kidney significantly contributes to the phenotypes observed in the global KO mice.…”