Direct and Indirect Inhibition of the Circadian Clock Protein PER1: Effects on ENaC and Blood Pressure.

Direct and Indirect Inhibition of the Circadian Clock Protein PER1: Effects on ENaC and Blood Pressure. Am J Physiol Renal Physiol. 2019 Feb 13;: Authors: Alli AA, Yu L, Holzworth MR, Richards J, Cheng KY, Lynch IJ, Wingo CS, Gumz ML Abstract Circadian rhythms govern physiological functions and are important for overall health. The molecular circadian clock is comprised of several transcription factors that mediate circadian control of physiological function in part by regulating gene expression in a tissue-specific manner. These connections are well established but the underlying mechanisms are incompletely understood. The overall goal of this study was to examine the connection between the circadian clock protein Per1, ENaC, and BP using a multi-pronged approach. Using global Per1 KO mice on a 129/sv background in combination with a high salt diet plus mineralocorticoid treatment, we demonstrate that loss of Per1 in this setting is associated with protection from hypertension. Next, we used the ENaC inhibitor benzamil to demonstrate a role for ENaC in BP regulation and urinary Na excretion in 129/sv mice. We targeted Per1 indirectly using pharmacological inhibition of Per1 nuclear entry in vivo to demonstrate altered expression of known Per1-target genes as well as a BP-lowering effect in 129/sv mice. Finally, we directly inhibited Per1 via genetic knockdown in amphibian distal nephron cells to demonstrate for the first time that r...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research