Kidney‐Specific KO of the Circadian Clock Protein BMAL1 Lowers Blood Pressure in Male C57BL/6J Mice

Abstract

All living organisms have an internal circadian clock that regulates the timing of many physiological functions. Dysregulation of circadian rhythms is associated with cardiovascular disease and cancer. Blood pressure (BP) has a circadian rhythm with a peak during the active phase and a dip during the rest phase. The core of the circadian clock consists of four core transcription factors: BMAL1, CLOCK, CRYTOCHROME (CRY), and PERIOD (PER). BMAL1 and CLOCK bind as a heterodimer to E‐box response elements of 40% of all expressed genes to regulate expression. PER and CRY act in a negative feedback loop, inhibiting the actions of BMAL1 and CLOCK. In 2007, Curtis et al. reported that global Bmal1 KO male mice had a 10 mmHg decrease in their mean arterial pressure (MAP) and lost their circadian rhythm of BP relative to control mice. Evidence from our laboratory and others suggest there is a link between the circadian clock in the kidney and BP regulation. We hypothesized that BMAL1 is critical for proper regulation of renal gene expression and that kidney‐specific KO of Bmal1 would alter BP. We generated kidney‐specific Bmal1 KO mice using Ksp‐cadherin Cre, which typically results in a distal nephron‐specific KO. Continuous BP measurements were made in the Cre+ kidney‐specific Bmal1 KO mice (KS‐Bmal1 KO) and the Cre‐ littermate control mice (CNTL) using radiotelemetry. Female CNTL and KS‐Bmal1 KO mice did not exhibit a detectable difference in MAP (~106 mm Hg in both genotypes, p=0.93, n=6 mice per group). Male CNTL mice exhibited a 24 hr MAP of 110 mm Hg whereas male KS‐Bmal1 KO mice had a 24 hr MAP of 99 mm Hg (P<0.001, n=5 CNTL, 7 KO). Kidney‐specific KO of Bmal1 did not appear to alter the circadian rhythm of BP in either gender. In response to a high salt diet plus mineralocorticoid treatment (HS/DOCP), male KS‐Bmal1 KO mice MAP increased by 10 mm Hg whereas the MAP for CNTL mice only increased by 4 mm Hg (P<0.01, n=3 CNTL, 7 KO). Female KS‐Bmal1 KO mice MAP did not change in response to HS/DOCP. These data suggest that kidney‐specific KO of Bmal1 increases sensitivity of male mice to salt and mineralocorticoid treatment. Preliminary metabolic cage data demonstrated that male KS‐Bmal1 KO mice retained urinary sodium during the first two days of HS/DOCP treatment whereas CNTL male mice continued to excrete increasing amounts of sodium (P<0.05, n=3 mice per genotype). The present study demonstrated that BMAL1 in the kidney likely acts in a sex‐specific manner and may not be important for circadian fluctuations in BP under the conditions tested. Together these results suggest that BMAL1 plays a critical role in the regulation of renal sodium reabsorption with important consequences for overall BP control.Support or Funding InformationNIH NIDDK R01DK109570 awarded to Michelle Gumz; NIH T32DK104721 awarded to Lauren Douma; American Heart Association Grant‐in‐aid awarded to Michelle Gumz; Gatorade Trust, 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.