Total Spectral Power and High Frequency Blood Pressure Variability is Reduced in Male Bmal1‐Collecting Duct Knock‐Out Mice During the Inactive Period

Abstract

Renal, cardiovascular, and autonomic functions are tightly regulated by both the master and peripheral circadian molecular clocks. Our group previously reported that loss of Bmal1 in the murine collecting duct resulted in lower mean blood pressures in male, but not female, mice. However, it is unclear if this clock dysregulation in the kidney can affect vascular pressure control mechanisms such as the autonomic nervous system. The current study tested the hypothesis that loss of Bmal1 in the collecting duct of the kidney would lower blood pressure variability in a time of day‐dependent manner in male mice. Collecting duct (principal cell) specific Bmal1 (Bmal1‐CDKO) mice were generated by crossing Bmal1 flox mice with aquaporin‐2 Cre mice. Between 10 and 16 weeks of age, telemetry transmitters were implanted and animals allowed to recover for two weeks. Animals were placed on a normal salt diet (0.49% NaCl) for 6 days and provided ad libitum food and water. Telemetry data was collected at 500 Hz for 2 minutes every 10 minutes. Data from the final 3 days was analyzed in Ponemah v6.41 (DSI Systems) to assess genotype and time of day‐dependent differences in blood pressure and blood pressure variability, which is indicative of autonomic function. Male flox control mice (n=7) and male Bmal1‐CDKO mice (n=7) had similar heart rates in the light/inactive period (ZT 2 to ZT10) and in the dark/active period (ZT14‐ZT22). Mean arterial pressure (MAP) was higher, albeit not statistically significant, during the active period in both groups (flox: 113.6 ± 1.1mmHg vs. Bmal1‐CDKO: 109.9 ± 1.2mmHg, p=0.07 by 2‐way ANOVA with Sidak post hoc). Bmal1‐CDKO mice had significantly lower MAP during the inactive period (96.8 ± 1.3mmHg) compared to flox controls (100.8 ± 1.2mmHg, p<0.05). Systolic blood pressure variability analysis found similar and consistent diurnal variations in low‐frequency and low‐frequency/high‐frequency spectral analysis in both Bmal1‐CDKO and flox control mice (p<0.05, 2‐way ANOVA with Sidak's post hoc). Blood pressure variability in the high‐frequency spectrum increased during the inactive period in flox control mice (A: 0.033 ± 0.005 mmHg2 v. I: 0.048 ± 0.01 mmHg2, p<0.05), but was similar between the active and inactive periods in Bmal1‐CDKO mice (A: 0.028 ± 0.003 mmHg2 v. I 0.034 ± 0.004 mmHg2). Total spectral power was similar in the active and inactive periods for flox control mice (A: 0.247 ± 0.004 mmHg2 v. I: 0.236 ± 0.009 mmHg2, p>0.05) but was significantly lower in the inactive period for Bmal1‐CDKO mice (A: 0.232 ± 0.006 mmHg2 v. I: 0.215 ± 0.004 mmHg2, p<0.05). Together, these data suggest an alteration in autonomic activity in the Bmal1‐CDKO mouse during the dark/ inactive period and provides evidence that dysregulation of peripheral clocks affects central nervous system function and output.Support or Funding InformationSupported by NIDDK T32 DK007545 to MKR, an AHA pre‐doctoral fellowship (18PRE33990345) to DZ, T32 HL007457 to BKB, and NHLBI P01 HL136267 to DMP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.