A Role for the Adrenal Clock in Aldosterone Regulation and Renal Excretory Function
Authors: Costello Hannah M. , Mckee Annalisse , Bratanatawira Phillip , Crislip Gene R. , Juffre Alexandria , Cheng Kit‐Yan , Wingo Charles S. , Gumz Michelle L. 
Published: May 2022

Purpose of study

It is well documented that most physiological functions, including hormone secretion, renal electrolyte excretion and blood pressure (BP), exhibit circadian rhythms. Disruption in these rhythms is associated with adverse cardiorenal outcomes. BMAL1 is a core circadian clock protein. Global BMAL1 knockout (KO) male mice exhibit lower and non‐dipping BP which is associated with inappropriate renal sodium (Na) retention (Zhang et al.). Kidney‐specific BMAL1 KO male mice displayed lower BP, but BP and renal Na excretion rhythm remained intact. The adrenal gland synthesizes the hormones, cortisol (corticosterone in rodents) and aldosterone, which exert a powerful influence on BP rhythm and renal electrolyte handling. Others have shown that the BMAL1 in the adrenal gland is necessary for proper regulation of corticosterone but the role of the adrenal clock in the regulation of aldosterone and renal function remains unknown.

Hypothesis

With kidney BMAL1 not playing a role in the inappropriate renal Na retention seen in global BMAL1 KO mice under basal conditions and unpublished data from our lab suggesting a crosstalk between the adrenal gland and kidney clock, we hypothesized a role for adrenal BMAL1 in maintenance of aldosterone and renal Na excretion rhythm.

Methods

To test this, adrenal‐specific aldosterone synthase Cre positive (AS)‐BMAL1 KO mice and Cre negative control mice were generated, and efficiency of KO was evaluated using immunohistochemistry and recombination PCR. AS‐BMAL1 male mice and littermate controls were placed in metabolic cages to assess urinary 12‐hour aldosterone excretion and renal Na and potassium (K) rhythm during normal Na diet and 7 days Na depletion. Furthermore, body weight, and 12‐hour food intake and water intake were measured (n=5‐6).

Results

Here, we show that efficiency of KO of adrenal BMAL1 was >80%, localized to the zona glomerulosa (ZG) of the adrenal gland. Body weight and water intake were similar between genotypes under normal Na or 7 days low Na conditions. There was an increase in food intake consumed during the inactive phase on both diets in AS‐BMAL1 KO mice compared with controls (ANOVA genotype effect p=0.0087), with no significant difference in 24‐hour food intake between genotypes. Urinary aldosterone levels were increased with blunted night/day differences in AS‐BMAL1 KO male mice under normal salt and low Na conditions compared with controls (ANOVA interaction p=0.0407). Na balance was calculated, showing a trend for a significant interaction between genotype and time (p=0.05), appearing more positive during their inactive period. K levels were not manipulated in the diet and there was no significant difference in K balance in AS‐BMAL1 KO mice under normal Na or 7 days low Na conditions (ANOVA interaction p=0.3808).

Conclusions

Consistent with our hypothesis, loss of the core clock protein BMAL1 in the ZG of the adrenal gland resulted in blunted night/day aldosterone levels and disturbance in renal Na handling. This work is the first to investigate the role of adrenal BMAL1 on aldosterone regulation and renal function, suggesting a link between the adrenal clock and the kidney. Future studies will assess whether BP rhythm in AS‐BMAL1 KO mice is disrupted and determine if there are sex‐specific differences in the role of adrenal BMAL1.