Circadian Rhythm, Clock Genes, and Hypertension: Recent Advances in Hypertension

Abstract

Accumulating evidence suggests that the molecular circadian clock is crucial in blood pressure (BP) control. Circadian rhythms are controlled by the central clock, which resides in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks throughout the body. Both light and food cues entrain these clocks but whether these cues are important for the circadian rhythm of BP is a growing area of interest. The peripheral clocks in the smooth muscle, perivascular adipose tissue, liver, adrenal gland, and kidney have been recently implicated in the regulation of BP rhythm. Dysregulation of the circadian rhythm of BP is associated with adverse cardiorenal outcomes and increased risk of cardiovascular mortality. In this review, we summarize the most recent advances in peripheral clocks as BP regulators, highlight the adverse outcomes of disrupted circadian BP rhythm in hypertension, and provide insight into potential future work in areas exploring the circadian clock in BP control and chronotherapy. A better understanding of peripheral clock function in regulating the circadian rhythm of BP will help pave the way for targeted therapeutics in the treatment of circadian BP dysregulation and hypertension.

Keywords: blood pressure; circadian rhythm; kidney diseases; suprachiasmatic nucleus; therapeutics.

Figure 1.. Core components of the circadian clock.

CLOCK and BMAL1 heterodimerize and bind E-box response elements within promoter regions of target genes, including Period and Cryptochrome (encoding PER1/2/3 and CRY1/2, respectively). In the negative feedback loops, PER and CRY heterodimerize and repress the activity of BMAL1 and CLOCK. This clock mechanism regulates tissue-specific target genes to regulate many physiological processes. Diagram created with Biorender.com.

Figure 2.. Cellular circadian clocks throughout the body, entrained by food cues, contributing to the circadian rhythm of blood pressure.

Blood pressure has a 24-hour cycle, peaking during the day and dipping by 10–20% during the night. Studies in rodents and humans suggest peripheral clocks within the vasculature, liver, adrenal glands, kidneys, microbiota in the gut, immune system, and autonomic nervous system contribute to regulation of the circadian rhythm of blood pressure (BP). These peripheral clocks can be entrained by food cues therefore, time-of-day feeding could be important for BP rhythm. Dysregulation of the circadian rhythm of BP is associated with adverse cardiorenal outcomes and increased risk of cardiovascular mortality. There are ongoing clinical trials to determine if chronotherapy will be beneficial for hypertension management and this should be expanded to whether it can correct any losses of BP rhythm. Diagram created with Biorender.com.