Renal Mechanism for Regulation of Blood Pressure by the Circadian Clock Protein PER1

Abstract

Work from our lab suggests that the clock protein PER1 is critical for maintaining the circadian rhythm of blood pressure (BP). BP is highest during the active phase of the day whereas during the rest period BP dips at least 10%. Individuals that do not experience the dip are termed “non‐dippers.” Non‐dipping hypertension is associated with an increased risk of cardiovascular disease. The mechanisms underlying non‐dipping hypertension are not understood. Male C57BL/6J Per1 KO mice develop non‐dipping hypertension on a high‐salt diet plus mineralocorticoid treatment (HS/DOCP). Sodium (Na) handling by the kidney has large effects on blood volume and BP. Excretion of Na also demonstrates a circadian pattern with a peak of excretion during active periods. We hypothesized that Per1 contributes to circadian regulation of BP via a renal Na handling‐dependent mechanism. To test this hypothesis, we treated WT and Per1 KO mice housed in metabolic cages with a normal salt diet or HS/DOCP. We measured changes in timed urinary Na excretion using flame photometry. The night:day ratio of Na in the urine of Per1 KO mice was decreased compared to WT (4x vs. 7x, P<0.001, n=6 per group). ELISA was used to measure the fold increase of urinary endothelin‐1 (ET‐1) in response to HS/DOCP treatment. Per1 KO mice exhibited a higher fold increase of ET‐1 compared to WT with HS/DOCP (5.9x vs 3.6x, P<0.01, n=9 WT, 11 KO). Using real‐time quantitative PCR, we determined that the expression of Na handling genes was altered in the KO mice on HS/DOCP. ET‐1 was upregulated in the cortex of Per1 KO mice on HS/DOCP treatment (P<0.01, n=6 per group). This upregulation was not present in WT mice on HS/DOCP. Nitric oxide synthase 1 (NOS1), a negative regulator of Na reabsorption, was significantly downregulated in Per1 KO medulla on HS/DOCP (P<0.05, n=6 per group). Preliminary data from the first distal‐nephron specific Per1 KO mice also shows an inappropriate increase in expression of the epithelial Na channel α subunit (αENaC) and the Na chloride cotransporter (NCC) relative to control mice. These results support our hypothesis that Per1 mediates control of circadian BP rhythms via the regulation of renal Na transport genes, specifically in the distal nephron of the kidney. These findings have implications for understanding the etiology of non‐dipping hypertension and the subsequent development of novel therapies for this dangerous pathophysiological condition.Support or Funding InformationR01DK109570; R21AG052861; American Heart Association Grant‐in‐aid; Gatorade Trust Fund, Division of Nephrology, Department of Medicine, University of FloridaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.