Circadian Clock Factor PER1 is involved in Crosstalk between the Kidney and Adrenal Glands

Abstract

Introduction Circadian clock proteins are transcription factors that play critical roles in the regulation of blood pressure, renal function, and hormone levels. Previously, we published that male mice with global knockout (KO) of the clock protein PER1 develop non-dipping hypertension in response to a high salt diet plus the mineralocorticoid DOCP (HSDOCP). HSDOCP treatment is a clinically relevant model of salt-sensitive hypertension. Global PER1 KO mice also exhibit inappropriately increased levels of aldosterone (Aldo) and decreased night:day ratio of urinary sodium (Na) excretion in response to HSDOCP. The objective of the present study was to examine the role of the kidney in PER1-mediated regulation of renal Na handling and Aldo levels. Hypothesis Kidney-specific KO of PER1 (KsPER1 KO) results in altered Aldo levels and decreased night:day rhythms of Na excretion in response to HSDOCP. Methods Ksp-cadherin Cre was used to generate KsPer1 KO mice. KO occurs in the distal nephron and collecting duct. KsPER1 KO (Cre +) mice were compared to control (CNTL) (Cre-) mice (all male; 2.5 months old). Baseline urine collections and plasma were collected on a normal salt diet (NS) and compared to similar samples collected after 3 days HS diet, followed by 3 days of HSDOCP treatment. Total RNA was isolated from adrenal glands (noon) for qPCR analysis. Results In contrast to global PER1 KO mice, the KsPER1 KO mice exhibited normal night:day urine Na excretion. However, KsPER1 KO mice exhibited increased Na retention vs CNTL (3.7 vs 2.7mEq, P<0.01). In response to HSDOCP, plasma Na significantly increased in KsPER1 KO (158 vs 164mM, P<0.05), but not in CNTL mice. HSDOCP treatment suppressed plasma Aldo in all mice, but KsPER1 KO mice displayed increased plasma Aldo vs. CNTL mice on both NS and HSDOCP treatment (NS: 21 vs. 12; HSDOCP: 4 vs. 2 pg/mL/gBW, P<0.01). Adrenal gland expression of the Aldo synthase gene, CYP11B2, was higher in KsPER1 KO vs CNTL (38%, P<0.05). Conclusions These results suggest that PER1 exerts kidney-specific action on renal Na handling independent of night:day effects. PER1 appears to be required for proper crosstalk between the kidney and adrenal gland to manage Aldo levels in response to HSDOCP. 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.