Sexual dimorphism in Bmal1 regulation of blood pressure and diurnal sodium handling in the rat

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB143

Poster Communications: Sexual dimorphism in Bmal1 regulation of blood pressure and diurnal sodium handling in the rat

D. M. Pollock1, C. Jin1, J. G. Johnston1

1. Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States.

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Previous studies suggest that core clock genes generally function to facilitate sodium (Na) conservation such as Per1 effects to mediate the renal effects of aldosterone. Bmal1 gene knockout mice have multiple pathologies, but little is known about 1) Bmal1 control of Na handling by the kidney, 2) Bmal1 function in the rat, or 3) possible sex differences in Bmal1 function in the kidney. Using Crispr/Cas9 methodology, we created a new whole-body Bmal1 knockout rat (Bmal1-/-) to determine the impact of Bmal1 gene deletion on the diurnal rhythms of urinary Na excretion (UNaV) in both acute and chronic salt loading conditions of male and female rats. Due to the importance of endothelin signaling in Na homeostasis, we also sought to determine the renal responses of our rats to endothelin B (ETB) receptor blockade for our chronic salt loading experiments. Male and female Bmal1-/- rats and littermate controls (Bmal1+/+) were implanted with telemetry transmitters to monitor mean arterial pressure (MAP). After a recovery period of at least one week, baseline urine samples were collected in 12hr light/dark intervals. The night-day difference in UNaV was evident in Bmal1+/+, but not Bmal1-/- male rats (404 ± 77 and -188 ± 56 µEq Na/12hr Bmal1+/+ vs. Bmal1-/-, n=13 and 10, respectively; P<.05). This loss of diurnal rhythm was not observed in female Bmal1-/- rats (266 ± 60 and 193 ± 61 µEq Na/12hr Bmal1+/+ vs. Bmal1-/-, n=10 and 9, respectively; P<.05). Unlike Bmal1-/- mice, Bmal1-/- rats displayed a normal circadian rhythm in MAP; however, MAP was lower in Bmal1-/- compared to Bmal1+/+, but was this difference was significant only in female rats. Rats given a single 900µEq Na load (p.o.) at the beginning of their inactive (Zeitgeber Time (ZT) 0) or active (ZT12) period. Both male and female, Bmal1+/+ and Bmal1-/- rats had a prompt natriuretic response to the salt load, excreting most of the salt in the first 12 hours at both ZT0 or ZT12. UNaV was significantly reduced in male Bmal1-/- rats on a normal or high salt diet during the active period compared to Bmal1+/+ rats. Addition of the ETB receptor antagonist, A-192621, to rats of both genotypes on a high salt diet caused significant hypertension and had no significant effect on UNaV. These data demonstrate that rats lacking Bmal1 expression display a blunted rhythm of diurnal UNaV in male but not female rats. Furthermore, this blunted rhythm may be due to a reduced amount of Na excretion during the active period.



Where applicable, experiments conform with Society ethical requirements.

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