Co‐regulation of Renal Function Genes by the Circadian Clock Protein PER1 and Aldosterone
Authors: Gumz Michelle L. , Douma Lauren G. , Holzworth Meaghan , Masten Sarah , Wu Gang , Hogenesch John B. , Cain Brian D. , Wingo Charles S. 
Published: June 2021

Hypertension is the leading cause of cardiovascular disease. A subset of hypertensive patients experience salt‐sensitive hypertension, which causes elevations in blood pressure (BP) after high salt intake. With large increases in dietary salt worldwide, the prevalence of hypertension has reached 30%. BP follows a circadian rhythm. The circadian clock is a highly conserved mechanism that allows organisms to adapt to the light/dark cycles of our environment. The molecular clock is comprised of core transcription proteins, such as the clock protein PER1. Further, the renin angiotensin aldosterone system (RAAS) is an important homeostatic mechanism to manage sodium and BP homeostasis. Previous results from our lab show that the circadian clock and RAAS both contribute to sodium and BP homeostasis. Based on these studies, we hypothesized that aldosterone and Per1 coordinately regulate genes that contribute to kidney function. We tested this hypothesis first by using a cell culture model from the renal cortical collecting duct. Cells were treated with aldosterone and/or siRNA to knockdown down PER1 expression. Using an unbiased microarray approach, we determined PER1 and aldosterone‐dependent changes in gene expression. Several hundred genes exhibited significant changes in expression in response to hormone treatment and PER1 knockdown. For the first time, we identified secreted frizzled related protein 1 (sFRP1), Claudin‐1, and Rhesus glycoprotein C (Rhcg) as target genes of aldosterone and PER1. The expression of sFRP1 demonstrated a 1.5‐fold increase in response to aldosterone (p<0.05, n=4), which was not affected in the absence of PER1, indicating that aldosterone and PER1 independently regulate sFRP1. In contrast, the 2.9‐fold (p<0.05, n=4) and 1.9‐fold (p<0.05, n=3) induction of Rhcg and Claudin‐1, respectively, by aldosterone was decreased significantly in the absence of PER1, suggesting that PER1 contributes to aldosterone‐mediated regulation of these genes. The ET‐1 gene is of particular interest due to its known role in the regulation of renal salt handling and BP. In the microarray study, knockdown of PER1 augmented the aldosterone response of ET‐1 mRNA by 3‐fold (p<0.05, n=4). Importantly, a similar effect was observed in the kidneys of Per1 knockout mice treated with a high salt diet plus an aldosterone analogue: loss of Per1 augmented the response of ET‐1 by 50% (p<0.01, n=6) compared to no change in WT mice. Interrogation of the database CircaDB revealed that Claudin‐1 and ET‐1 are both expressed with a significant circadian rhythm in the kidney (p<0.001). Together these data demonstrate that multiple genes critical to renal function are co‐regulated by the circadian clock PER1 and RAAS. These data may have important implications for understanding the underlying mechanisms of, and designing novel treatments for, salt‐sensitive hypertension in humans.Support or Funding InformationR01DK109570; R21AG052861; American Heart Association Grant‐in‐aid; Gatorade Trust Fund, Division of Nephrology, Department of Medicine, University of Florida; NF/SG VAMCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.