Kidney-Specific KO of the Circadian Clock Protein PER1 Alters Renal Sodium Handling, Aldosterone Levels, and Kidney/Adrenal Gene Expression

PER1 is a circadian clock transcription factor that is regulated by aldosterone, a hormone that increases blood volume and sodium retention to increase blood pressure. Male global Per1 knockout (KO) mice develop reduced night/day differences in sodium excretion in response to a high salt diet plus desoxycorticosterone pivalate treatment (HS+DOCP), a model of salt-sensitive hypertension. Additionally, global Per1 KO mice exhibit higher aldosterone levels on a normal salt diet. To determine the role of Per1 in the kidney, male kidney-specific Per1 KO (KS-Per1 KO) mice were generated using Ksp-cadherin Cre recombinase to remove exons 2-8 of Per1 in the distal nephron and collecting duct. Male KS-Per1 KO mice have increased sodium retention, but have normal diurnal differences in sodium excretion in response to HS+DOCP. The increased sodium retention is associated with altered expression of glucocorticoid and mineralocorticoid receptors, increased serum aldosterone, and increased medullary endothelin-1 compared to control (CNTL) mice. Adrenal gland gene expression analysis revealed that circadian clock and aldosterone synthesis genes have altered expression in the KS-Per1 KO mice compared to CNTL mice. These results emphasize the importance of the circadian clock, not only in maintaining rhythms of physiological functions but also for adaptability in response to environmental cues, such as HS+ DOCP, to maintain overall homeostasis. Given the prevalence of salt-sensitive hypertension in the general population, these findings have important implications for our understanding of how circadian clock proteins regulate homeostasis.