Most of us go to sleep and wake up around the same time every day, even on the weekends when we try to sleep in. When we change our schedule to either wake up earlier or because we stay up late (probably tweaking grant submissions at the last possible moment, or a busy night on-call), we can exhibit physical symptoms such as fatigue. You can thank your internal biological clock for that. Twenty-four-hour biological clocks, also known as circadian clocks, not only regulate our sleep/wake cycle, but also regulate many other physiological functions including hormone release, body temperature, and digestion. Nearly all life on Earth evolved circadian clocks to adapt to the various phases of a 24-hour cycle of Earth. Our clocks are entrained by various cues from the environment including light, food, and exercise. These external cues tell our clocks what time of the day it is to help sync their actions. Light cues are recognized by the hypothalamus, which in turn send neuronal and hormonal signals to the peripheral clocks. One of these peripheral clocks is the kidney clock. Circadian rhythms of sodium excretion, blood pressure, and glomerular filtration rate are observed in humans, to which the kidney clock contributes.
When our internal circadian clock does not match up with the environment around us we can experience symptoms such as fatigue, slower cognitive abilities, and we become more susceptible to contracting illness. Disruption of the circadian clocks is seen in individuals who suffer from jet-lag and in those who work night shifts. Chronic disruption of our circadian clocks has been shown to have negative effects on our health. Millions of Americans either permanently work night shift or alternate between day and night shift work. This population is expected to grow in our increasingly 24/7 modern society. Multiple observational studies have shown a relationship between shift work and increased risk for metabolic syndrome, cancer, and heart disease. In addition, populations with disease experience circadian disruption. It has been observed that individuals with chronic kidney disease have a higher prevalence of non-dipping hypertension (absent or blunted dip in blood pressure at night), suggesting disturbances in their circadian rhythm.
In 2017, three scientists, Jeffery Hall, Michael Young, and Michael Roshbash, were awarded theNobel Prize in Medicinefor their work on the molecular basis of the circadian clock. Specifically, they identified the first circadian gene in fruit flies, Period. At a molecular level, the clock is composed of a set of core transcription factors. These transcription factors work in feedback loops to not only regulate their own transcription, but also the transcription of approximately 50% of all expressed genes. In Dr. Michelle Gumz’s laboratory we study how these circadian transcription factors help to kidney function. Our lab and others have shown that the kidney clock is critical in controlling cycles of sodium reabsorption and excretion, which affects blood pressure (Douma et al. 2018). In fact, if scientists genetically deleted any of the core clock genes (Periodfor example) in mouse models, it generally results in a change in pressure (both hypertension or hypotension depending on the clock gene that is knocked out). In human subjects, non-dipping hypertension has been associated with adverse cardiovascular outcomes and increased risk for chronic kidney disease. This can be modeled in the lab by using male mice where we have genetically deleted the circadian clock transcription factor PERIOD1 (they are called Per1 knockout mice). These mice when placed on a high salt diet and given exogenous mineralocorticoids develop a non-dipping, salt-sensitive hypertension (Douma et al. 2018). The high salt plus mineralocorticoid excess reflects a high aldosterone, low renin state which is often seen in salt-sensitive hypertension patients, and is quite prevalent in African-Americans. Additionally, these mice have altered night/day ratios of sodium excretion, also seen in human cases of non-dipping hypertension. These types of basic science experiments and models allow us to better understand the regulation of circadian rhythms in the body, and how disruption of these rhythms can manifest as diseases.
By studying how the circadian clocks regulate physiological functions, like blood pressure regulation, we can uncover new pharmaceutical targets or determine the best time for medication to be taken. Chronotherapy, or the specific timing of when medications should be taken, has the potential to improve efficiency of the medication and/or to reduce side effects. The circadian clock regulates the tissue-specific expression of thousands of genes, including genes that express the targets of medications or the proteins that break down medications. Indeed, many of the most popular medications in the United States target molecules that are regulated by the circadian clock. For example, the most widely prescribed drug class, statins, targets HMG CoA Reductase, which exhibits a rhythm in expression in the liver. While more randomized controlled studies are needed, published studies on chronotherapy have interesting findings. There is growing evidence suggesting that taking blood pressure medication at night vs in the morning can assist in restoring the nighttime dip in those that have non-dipping hypertension, while still protecting them from the morning surge in blood pressure. Recently, a review was published that compared all of the trials from 2013-2017 that looked at the effect of nighttime dosing on 24-hour blood pressure. While there are some inconsistencies (highlighting that more randomized trials with higher statistical power need to be performed), overall the studies did show that nighttime dosing had an overall positive impact on 24-hour blood pressure (Bowles et al., 2018). Even though these studies were focused on hypertension, research suggests that other medications may be more effective and/or less toxic if given at a specific time, such as chemotherapies. Studying the mechanisms behind how the clock controls physiological functions in combination with research into timing of medication dosing could be quite powerful in treating diseases.
Lauren Douma, PhD @DoumaPhD
University of Florida