Abstract 096: Adrenal-specific KO Of The Circadian Clock Protein Bmal1 Alters Blood Pressure Rhythm

Abstract

BMAL1 is a core circadian clock protein that regulates most physiological functions, including blood pressure (BP). Global BMAL1 knockout (KO) male mice exhibit reduced, non-dipping BP and loss of diurnal rhythm of renal sodium (Na) excretion. Although, BP and renal Na excretion rhythm remained intact in kidney-specific BMAL1 KO male mice. The adrenal gland synthesizes hormones which influence BP rhythm and renal electrolyte handling. The role of adrenal BMAL1 in the regulation of BP and renal function remains unknown. The goal was to test the hypothesis that adrenal BMAL1 is required for normal circadian rhythms of BP and renal Na excretion. Adrenal-specific aldosterone synthase Cre positive (AS)-BMAL1 KO male mice ( n =5) and littermate Cre negative, floxed control (CNTL) male mice ( n =6) underwent a telemetry study to measure BP. Cosinor analysis was performed to assess BP rhythms. During telemetry recordings, mice were placed in metabolic cages for 5 days on a normal salt diet. The latter 3 days, 12 h urine samples were collected before each light-dark Zeitgeber (6AM and 6PM/ Zeitgeber Time (ZT)0 and ZT12) to measure night/day patterns in renal Na excretion. Kidneys were collected from a separate cohort of mice ( n =7-8/genotype) at ZT0 and ZT12 for gene expression analysis of key Na transporters. No BMAL1-dependent changes in the 24 h averages for BP were observed. Cosinor analysis revealed significant differences in BP rhythm, however. The period (time taken for a full circadian cycle, ~24 h) was significantly shortened for BP in AS-BMAL1 KO mice vs. CNTL (23 h 31 vs 24 h 16, p =0.01). Acrophase (the time at which BP peaks) was shifted ~2 hours later in KO mice (KO ZT17 h 38 vs CNTL ZT15 h 45, p =0.002). The MESOR (midline estimating statistic of rhythm) of BP remained similar between groups (KO 133.5 mmHg vs CNTL 132.7 mmHg, p =0.904). Day/night Na excretion was not different in AS-BMAL1 KO mice vs. CNTL (ANOVA interaction p =0.168). This was consistent with a lack of genotype effects on gene expression for NCC, α, β, or γ ENaC. Significant time of day effects were observed for all 4 genes (all with p <0.001). In conclusion, BMAL1 KO in the adrenal gland altered BP rhythm, with no changes in renal Na excretion. This work is the first to investigate the role of adrenal BMAL1 on BP regulation.