Abstract P174: Loss of Bmal1 in the Collecting Duct Lowers Blood Pressure in Male, but Not Female, Mice

Abstract

Kidney function follows a 24-hour rhythm that is subject to regulation by so-called circadian clock genes. Previous studies suggested a potential role of circadian gene Bmal1 in regulating renal excretory function and blood pressure, yet the mechanism is not completely clear. Our lab showed that high salt diet induces a phase shift in Bmal1 expression in the renal inner medulla that is dependent on endothelin B receptor (ET B ) function. In addition, the ET B receptor-mediated natriuretic effect is time-of-day- and sex-dependent. We recently generated a mouse model that lacks Bmal1 expression in principal cells of the renal collecting duct, which has the highest concentration of ET B receptor. The current study was designed to test the hypothesis that Bmal1 in the collecting duct regulates blood pressure in a sex-dependent manner. Male (n=8-9) and female (n=6) collecting duct Bmal1 knockout (CD Bmal1 KO) and floxed control (flox) mice were implanted with telemetry transmitters, and fed normal salt (0.49% NaCl) diet (NS) for 6 days, followed by 6 days of high salt (4% NaCl) diet (HS). After this period, mice were treated with an ET B receptor antagonist (A-192621; 30mg/kg/day) for another 6 days. At the end of the study, we performed cosinor analysis on telemetry data collected throughout the study. Under NS, male CD Bmal1 KO showed significantly lower 24-hr mean arterial pressure (MAP) compared to flox (105±1 vs 112±1 mmHg, p=0.01). However, we did not observe any significant differences in the MAP of female mice (106±1 vs 108±1 mmHg, p=0.26). Under HS, MAP of male CD Bmal1 KO was significantly lower compared to flox (107±1 vs 114±1, p=0.01). No significant differences were observed in female mice (109±1 vs 110±1 mmHg, p=0.63). In male CD Bmal1 KO, the increase in MAP in response to the ET B receptor antagonist was significantly attenuated compared to flox (124±1 vs 130±1 mmHg, p<0.01). However, the increase in MAP in female mice was not significantly different between CD Bmal1 KO and flox (130±1 vs 127±2 mmHg, p=0.33) during ET B blockade. There were no differences in the amplitude of diurnal MAP between genotype in either sex on any diet. These data suggest that collecting duct Bmal1 plays an important role in blood pressure regulation in male, but not female, mice.