Renal Distal Segment-Specific BMAL1 Regulates Blood Pressure in the Setting of Potassium Depletion

Introduction Circadian clock factors in the kidney influence systemic blood pressure control. BMAL1 is a core mammalian circadian gene responsible for tissue‐specific transcription regulation. Previously, we generated renal distal segment BMAL1 knockout mice (dsBMAL1 KO) that exhibit lower blood pressure compared to control mice (CNTL) in males but not females. Additionally, male dsBMAL1 KO retain less sodium following potassium depletion compared to CNTL, a difference not seen in females. Goal The goal of this study was to determine if dysregulation of the renin‐angiotensin‐aldosterone system (RAAS) contributes to the sex‐specific solute handling response to potassium depletion and to test the hypothesis that male dsBMAL1 KO display lower blood pressure than CNTL adapted to a potassium deficient diet. Methods Our mouse model was generated using floxed exon 8 BMAL1 mice crossed with kidney‐specific cadherin Cre+ mice to generate dsBMAL1 KO. Floxed Cre‐littermates were used as CNTL. Arterial blood samples from 14–18 week old male and female mice were collected at noon for basal and 5 days post potassium depletion for serum measurements (0% K, 0.2% Na; N=4–8). Additional male mice were implanted with telemeter devices for 24‐hour monitoring of blood pressure before and during administration of a potassium depleted diet over 5 days (N=7–8). Two‐way ANOVA was used to compare diet and genotype effects within each sex. Results Serum angiotensin II levels were unchanged following potassium depletion regardless of genotype or sex. As expected, serum aldosterone levels were lower following potassium depletion compared to baseline in males and females (M: P<0.0001; F: p<0.01), however, there was no difference between genotypes (M: P=0.5; F: P=0.8). Interestingly, potassium depleted males had higher serum aldosterone at midnight compared to noon (P<0.001), however, there was no time difference in females (P=0.8). Following potassium depletion in males, systolic blood pressure significantly decreased in both genotypes (P<0.0001), but a greater decrease over the treatment period was observed in dsBMAL1 compared to CNTL (CNTL: 125±2.4 to 121±1.4; KO: 123±1.7 to 116±1.7 mmHg; P INTERACTION <0.05). Conclusions BMAL1 in renal distal segments contributes to blood pressure regulation. Potassium depletion decreases blood pressure in this experimental setting with male dsBMAL1 KO demonstrating a greater drop in pressure than CNTL. These data suggest RAAS does not contribute to genotype‐dependent differences seen in blood pressure following potassium depletion. Support or Funding Information NIH/NIDDK, 1R01DK109570‐01A1; 19POST34450134 AHA Postdoc Fellowship; 5T32HL083810‐10 Postdoc Training Grant, Gatorade Trust through the UF Department of Medicine, North Florida/South Georgia Veterans Health Systems