Loss of circadian gene Bmal1 in the collecting duct lowers blood pressure in male, but not female, mice

Kidney function follows a 24-h rhythm subject to regulation by circadian genes including the transcription factor Bmal1. A high-salt diet induces a phase shift in Bmal1 expression in the renal inner medulla that is dependent on endothelin type B (ETB) receptors. Furthermore, ETB receptor-mediated natriuresis is sex dependent. Therefore, experiments tested the hypothesis that collecting duct Bmal1 regulates blood pressure in a sex-dependent manner. We generated a mouse model that lacks Bmal1 expression in the collecting duct, where ETB receptor abundance is highest. Male, but not female, collecting duct Bmall knockout (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 Cl)Bmal1KO 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). ETB receptor 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 ETB blockade (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 duct Bmall has no role in circadian MAP but plays an important role in overall blood pressure in male, but not female, mice.