Differences in renal BMAL1 contribution to sodium homeostasis and blood pressure control in male and female mice.

The renal circadian clock has a major influence on the function of the kidney. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL; or BMAL1) is a core clock protein and transcription factor that regulates the expression of nearly half of all genes. Using male and female kidney-specific cadherin BMAL1 knockout mice (KS-BMAL1 KO), we examined the role of renal distal segment BMAL1 in blood pressure control and solute handling. We confirmed that this mouse model does not express BMAL1 in the thick ascending limb, distal convoluted tubule, and collecting duct cells which are the final locations for solute and fluid regulation. Male KS-BMAL1 KO displayed a substantially lower basal systolic blood pressure (SBP) compared to littermate control mice (CNTL), yet their circadian rhythm in pressure remained unchanged [Male: CNTL 127±0.7 (5) vs. KS-BMAL KO 119±2.3 mmHg (4); p<0.05]. Female mice, however, did not display a genotype difference in basal SBP [F: CNTL 120±1.6 (7) vs. KS-BMAL1 119±1.5 mmHg (5); p=0.4]. In addition, male KS-BMAL1 KO had less sodium retention compared to CNTL in response to a potassium-restricted diet (15% less following 5 days of treatment). However, there was not a genotype difference in sodium handling after a potassium-restricted diet in female mice. Furthermore, there is evidence indicating a sex-specific response to potassium restriction where females reabsorb less sodium in response to this dietary challenge compared to males. We propose that BMAL1 in the distal nephron and collecting duct contributes to blood pressure regulation and sodium handling in a sex-specific manner.