Loss of circadian geneBmal1in the collecting duct lowers blood pressure in male, but not female, mice

Jan 7, 2020American journal of physiology. Renal physiology

Losing the daily rhythm gene Bmal1 in kidney water-collecting cells lowers blood pressure in male but not female mice

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Abstract

Male collecting duct knockout mice had significantly lower 24-h mean arterial pressure (MAP) compared to flox controls.

A high-salt diet induced a phase shift in endothelin receptor expression in the renal inner medulla.
Endothelin receptor-mediated natriuresis is associated with sex differences.
After 6 days on a high-salt diet, male knockout mice exhibited lower MAP than male flox controls, while female mice showed no significant differences.
Endothelin receptor blockade increased MAP similarly in both male and female mice, but male knockout mice still maintained lower MAP than male flox controls.
No significant differences in the amplitude or phase of MAP were observed between genotypes in either sex.

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Kidney function follows a 24-h rhythm subject to regulation by circadian genes including the transcription factor. A high-salt diet induces a phase shift inexpression in the renal inner medulla that is dependent on endothelin type B (ET) receptors. Furthermore, ETreceptor-mediated natriuresis is sex dependent. Therefore, experiments tested the hypothesis that collecting ductregulates blood pressure in a sex-dependent manner. We generated a mouse model that lacksexpression in the collecting duct, where ETreceptor abundance is highest. Male, but not female, collecting ductknockout (CDBmal1KO) mice had significantly lower 24-h mean arterial pressure (MAP) than flox controls (105 ± 2 vs. 112 ± 3 mmHg for male mice and 106 ± 1 vs. 108 ± 1 mmHg for female mice, by telemetry). After 6 days on a high-salt (4% NaCl) diet, MAP remained significantly lower in male CDBmal1KO mice than in male flox control mice (107 ± 2 vs. 113 ± 1 mmHg), with no significant differences between genotypes in female mice (108 ± 2 vs. 109 ± 1 mmHg). ETreceptor blockade for another 6 days increased MAP similarly in both male and female CDBmal1KO and flox control mice. However, MAP remained lower in male CDBmal1KO mice than in male flox control mice (124 ± 2 vs. 130 ± 2 mmHg). No significant differences were observed between female CDBmal1KO and flox mice during ETblockade (130 ± 2 vs. 127 ± 2 mmHg). There were no significant genotype differences in amplitude or phase of MAP in either sex. These data suggest that collecting ducthas no role in circadian MAP but plays an important role in overall blood pressure in male, but not female, mice. Bmal1Bmal1Bmal1Bmal1Bmal1Bmal1B B B B B

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Loss of circadian geneBmal1in the collecting duct lowers blood pressure in male, but not female, mice

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