17‐β‐Estradiol Causes a Moderate Increase in Blood Pressure in Kidney‐Specific BMAL1 Knockout and Control Mice in Response to Potassium Depleted, High Salt Diet

Abstract

Blood pressure (BP) regulation is influenced by circadian clock factors. Previously, we reported a sex-specific BP response in kidney-specific BMAL1 knockout mice (KS-BMAL1 KO) where male KS-BMAL1 KO exhibited lower BP than control mice but females lacked this difference. BMAL1 is a core mammalian circadian transcription factor responsible for the tissue-specific regulation of thousands of genes. The goal of this study was to determine if female sex hormones, specifically 17-β-estradiol, contributes to the lack of BP response in female mice. We hypothesize that ovariectomy (OVX) without estradiol supplementation will replicate the phenotype found in male mice and reveal a genotype effect in females. OVX and subcutaneous pellet implantation was performed using either placebo or estradiol pellets (0.1 mg/60 day release) in adult female KS-BMAL1 KO and control mice. After recovery, telemetry devices were implanted. Mice were administered a potassium depleted, high salt diet (0KHS) regimen (0% K, 2% Na, N=3-4). Telemetry recordings of BP demonstrated mean arterial pressure was approximately 5±1 mmHg higher in estradiol treated mice compared to placebo (P=0.02). There was a trend that suggests estradiol exacerbates the BP response following 0KHS (P=0.05). There were no genotype differences. Estradiol supplementation increased heart rate in both genotypes by 11±4% (P=0.0001). Heart rate decreased by 21±2% in all groups following 0KHS treatment (P<0.0001). Differences in locomotor activity were not detected between any groups. Because there were no reported genotype differences, KS-BMAL1 KO and control mice data were combined to determine the effect of hormone replacement therapy on BP over the course of the whole treatment period. Two-way repeated measures ANOVA showed that estradiol supplementation increased BP in response to 0KHS (Interaction P=0.0002; Figure). In conclusion, our results indicate that BMAL1 does not play a role in estradiol regulated BP control contrary to our hypothesis. Surprisingly, estradiol supplementation leads to higher BP in a potassium depleted, high salt environment. These differences in BP may be related to estradiol-induced changes in heart rate. These findings provide insight on the previously reported sex-specific response to KS-BMAL1 KO in BP control. Importantly, the effect of estradiol supplementation on BP in this model of salt-sensitive hypertension must be further investigated due to the possible implications for post-menopausal BP regulation.