Decreased Night:Day Urinary Sodium Excretion in Male Mice with KO of the Circadian Clock Gene Per1 is Associated with Altered Night:Day Urinary Excretion of Endothelin‐1
Authors: Douma Lauren G , Lynch I Jeanette , Cheng Kit‐Yan , Barral Dominique , Masten Sarah , Holzworth Meaghan , Cain Brian D , Wingo Charles S , Gumz Michelle L 
Published: June 2021

The circadian clock, which regulates many physiological functions throughout a 24‐hour period, is comprised of a core set of transcription factors. These transcription factors regulate not only their own expression, but also the expression of thousands of other genes in a tissue‐specific manner. One of these core transcription factors is PERIOD1 (PER1). Our laboratory has previously reported that global KO of the Per1 gene in C57BL/6 male mice results in the development of non‐dipping hypertension in response to a high salt diet plus mineralocorticoid treatment (HS/DOCP). Additionally, the non‐dipping hypertension is accompanied by a decreased night:day ratio in urinary sodium excretion. Endothelin‐1 (ET‐1) has a variety of tissue‐specific roles. In the vasculature it is known to cause vasoconstriction, whereas in the kidney it stimulates natriuresis by inhibiting the epithelial sodium channel (ENaC). In response to the HS/DOCP treatment, Per1 KO mice have increased ET‐1 expression (37% increase) in the kidney compared to WT mice as measured by real‐time PCR (noon timepoint, n=6 per group, p<0.05). This increase in ET‐1 expression during the day resulted in a significantly decreased night:day urinary ET‐1 excretion in the Per1 KO mice compared to WT mice in response to HS/DOCP treatment (8.3 vs. 3.8, n=6 per group, p<0.05). We hypothesize that timing of ET‐1 expression is critical for maintaining normal night:day sodium excretion. Mice with a collecting duct KO of ET‐1 using aquaporin‐2 cre recombinase did not have an altered night:day sodium excretion compared to floxed ET‐1 littermates (n=5–6 per group, p>0.05), however CD ET‐1 KO did develop a more positive sodium balance relative to control mice in response to HS/DOCP (n=5–6 per group, Pslope = 0.003). To determine the role of increased ET‐1 expression in the global Per1 KO mice on HS/DOCP, we generated Per1 KO mice with a collecting‐duct specific ET‐1 KO (Global Per1/CD ET1 KO). Preliminary data indicate that at baseline, the Global Per1/CD ET1 KO mice have decreased αENaC (50% decrease) and endothelin A receptor expression (30% decrease) in addition to increased endothelin B expression (60% increase) compared to Per1 KO mice (noon timepoint, n=3–5 per group, p<0.05). This new mouse model will allow us to test the hypothesis that increased ET‐1 expression in the Per1 KO is leading to the altered night:day sodium excretion. We would expect KO of CD ET‐1 to restore normal night:day sodium excretion in Per1 KO mice. Understanding the role of the circadian clock on ET‐1 expression associated with non‐dipping hypertension will provide insight into this important disorder and potentially lead to novel therapeutic targets.

Support or Funding Information

NIH T32DK104721 (LGD), AHA 18POST34030210 (LGD), NIH/NIDDK 1R01DK109570 (MLG), The Gatorade Trust through the UF Department of Medicine.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.