Abstract P003: Kidney-specific Knockout Of The Clock Protein Bmal1 Is Protective In Salt-sensitive Hypertension

Abstract

Intro: Circadian clock factors, such as BMAL1, influence systemic blood pressure (BP) control. Previously, we generated renal distal segment BMAL1 knockout mice (KS-BMAL1 KO) that exhibit lower BP compared to control mice (CNTL) in males but not females. Additionally, male KS-BMAL1 KO retain less sodium following potassium depletion compared to CNTL, a difference not seen in females. Goal: The goal of this study was to test the hypothesis that male KS-BMAL1 KO display lower BP than CNTL in response to a potassium deficient, high salt diet. Methods: Our mouse model was generated using floxed exon 8 BMAL1 mice crossed with kidney-specific cadherin Cre+ mice to generate KS-BMAL1 KO. Floxed Cre- littermates were used as CNTL. Male mice were implanted with telemeter devices for 24-hour BP monitoring before and during administration of a low potassium diet over 7 days (0% K, 0.2% Na) and followed by a low potassium, high salt diet for 10 days (0% K, 2% Na, N=7-8). Two-way ANOVA was used to compare diet and genotype effects. Results: Following potassium depletion alone, systolic BP significantly decreased in both genotypes (P<0.05). Compared to baseline, KS-BMAL KO did not exhibit the increase in BP as seen in CNT on the potassium deficient, high salt diet (CNTL: 125±2 to 132±1; KO: 123±2 to 122±2 mmHg). Neither diet nor genotype altered circadian rhythms in BP. Conclusions: BMAL1 in renal distal segments contributes to BP regulation. KS-BMAL1 KO appear to be protected from the substantial increase in BP that occurred in CNTL in response to a low potassium/high salt diet. These data suggest that BMAL1 contributes to the protection from salt-sensitive hypertension in the setting of a low potassium diet.