Adrenal-Kidney Clock Crosstalk: Utilizing Tissue-Specific Clock KO Models
Authors: Costello Hannah , Crislip G. Ryan , Mckee Annalisse , Cheng Kit-Yan , Juffre Alexandria , Johnstone Jermaine , Douma Lauren , Gumz Michelle 
Published: May 2023

Circadian rhythms are 24-hour oscillations that regulate many physiological functions including hormone signaling and electrolyte excretion. These rhythms are coordinated by a molecular clock, comprised of 4 key core clock proteins – BMAL1, CLOCK, CRY, and PER. Our lab investigates the role of the adrenal and kidney clocks on renal function. Previous data from the lab has shown that kidney-specific knockout (KO) of PER1 led to increased renal sodium retention in male mice which was associated with increased serum aldosterone and increased expression of aldosterone synthesis genes in the adrenal gland. Interestingly, these mice also displayed altered adrenal clock gene expression. This led to our hypothesis that adrenal-kidney clock crosstalk exists with implications for the regulation of renal and adrenal function.To test this, we utilized adrenal (AS)- and kidney-specific (KS) Bmal1 KO mouse models to assess clock genes in the adrenal glands and kidneys of these mice. Kidney, separated into cortex and medulla, from AS- Bmal1 KO male and adrenal glands from KS- Bmal1 KO male mice and littermate Cre negative, floxed control mice ( n=7-8/genotype) were collected at 6AM (lights on) and 6PM (lights off). RNA was isolated from tissue for clock gene expression analysis using qPCR, specifically Bmal1, Clock, Cry1, Cry2 and Per1, and analyzed using 2-way ANOVA with Sidak multiple comparisons post hoc analysis.Here, we show significant differences in clock gene expression between the kidney cortex and medulla of AS- Bmal1 KO male mice compared with controls. There was a significant interaction between time and genotype for Bmal1, Clock and Cry1 expression with post hoc analysis showing increases in Bmal1 ( p=0.0070) and Cry1 ( p=0.0235) at 6AM in KO animals vs. controls, whereas Clock was significantly decreased at 6PM ( p=0.0108). A similar change was seen with medulla Bmal1 expression, but there was a significant interaction in medulla Per1 showing significant increases at 6PM ( p=0.0465). Interestingly, KS- Bmal1 KO mice displayed significant genotype effects in both adrenal Bmal1 and Clock with post hoc analysis showing decreases at 6AM ( p=0.0035, and p<0.0001, respectively).Tissue-specific KO of BMAL1 has distinct effects on the clock in different peripheral tissues, challenging the current paradigm of the clock mechanism and suggesting that the clock may function differently across tissues. Furthermore, these data support our hypothesis that adrenal-kidney clock crosstalk exists as knocking out BMAL1 in adrenal gland resulted in changes in clock gene expression in the kidney and vice versa. Future work will utilize these tissue-specific Bmal1 KO models to focus on whether peripheral clock cross talk differs between males and females and whether it contributes to regulation of renal and adrenal function.

AHA, NIDDK

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.