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

Abstract

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.

A Role for the Circadian Clock Protein Per1 in the Regulation of the NaCl Co-transporter (NCC) and the with-no-lysine Kinase (WNK) Cascade in Mouse Distal Convoluted Tubule Cells

“…Consequently, we have shown previously that Per1 KO mice exhibit significantly lower BP (8) and increased urinary sodium levels and urine volume (9) compared with WT controls. Consistent with these results, we have shown recently that mice with reduced levels of Per1 have a defect in renal sodium retention and decreased plasma aldosterone (17).…”

“…We have demonstrated that inhibition of Per1 results in up-regulation of Cry1/2 mRNA and protein levels and that Per1 and Cry2 mediate opposing actions on target gene expression in the kidney, liver, and adrenal glands in vitro and in vivo (16,17). However, this has not been investigated in the context of CK1␦/⑀ inhibition in vitro in mDCT15 cells or in in vivo in kidney cortex.…”

Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways

“…Cry1/2 knockout mice developed salt-sensitive hypertension, whereas Per1 heterozygous knockout mice exhibited hypotension with impaired renal Na ϩ conservation associated with reduced plasma aldosterone (97). Notably, Per1 heterozygous knockout mice expressed higher levels of WNK4, depressed NCC expression in the kidneys, and increasing urinary Na ϩ excretion and hypotension (98).…”

Tick Tock

“…Moreover, it is strongly associated with the development of left ventricular hypertrophy, which, in turn, is linked to cardiovascular morbidity and mortality in kidney transplant recipients-specifically to sudden cardiac death. 15,16 The increase in sudden death is believed to be due to increased myocardial mass, cardiac fibrosis, increased arrhythmogenicity, and reduced diastolic filling of the coronary circulation. Prevention of vascular calcification, uremic cardiomyopathy, and sudden cardiac death are the leading challenges in the management of patients with CKD.…”

“…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.…”