Tick Tock Goes the Circadian Clock

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Hannah Costello, PhD
Postdoctoral Fellow, University of Florida

Chronic kidney disease commonly occurs with aging. The aging population is increasing, with the World Health Organization stating that the population of adults  aged 60 and older will increase from 12% in 2015 to 22% in 2050. Consequently, physicians are seeing more and more patients with decreased kidney function and age-associated histological changes in the kidney including nephrosclerosis, nephron hypertrophy, and a decline in the number of functional nephrons (Denic et al., 2016). In addition to functional and structural changes in the kidney, alteration in circadian rhythms in renal physiological parameters have been reported with aging including, but not limited to, dampened electrolyte rhythms and increased nighttime urine excretion (nocturia) (reviewed in (Mohandas et al., 2022)). The mechanisms that contribute to these altered circadian rhythms in aging though, are poorly understood.

How does your body know what time it is, anyway? Does the body’s ability to know what time it is change as we age? There are internal circadian clocks in nearly every cell in our body (Partch et al., 2014), including cells within the kidney, that regulate many physiological functions including sleep/wake cycles, blood pressure, hormone release, and aspects of renal function such as electrolyte handling and glomerular filtration rate (Solocinski and Gumz, 2015). These clocks can be synced to the time-of-day by external cues, such as light, food, and exercise. The central clock, which is the suprachiasmatic nucleus that resides in the hypothalamus, is entrained by light and acts as the conductor of a circadian orchestra, where the instruments are the cellular clocks in peripheral tissues. But now, researchers are challenging this paradigm and asking questions about the control of circadian rhythms in the body – do these peripheral clocks have other conductors? Can they go solo? The knowledge behind the regulation and function of peripheral clocks has advanced over the last decade however, there is still little known about what makes the kidney clocks tick, what happens to these clocks when we age, and whether these processes contribute to dampened renal rhythms seen in aging (Hood and Amir, 2017).

Tissue clocks are often referred to in the singular such as “the kidney clock”, but with the heterogeneity of the kidney with many different cell types, it is reasonable to speculate that there is heterogeneity of the clocks within the kidney. Therefore, understanding how these kidney clocks are regulated is challenging (recently reviewed in (Costello et al., 2022)). To date, studies have found the central clock (entrained by light) can synchronize the kidney clocks (Wu et al., 2010), but it has been shown that the kidney clocks can oscillate without the central clock as well (Yoo et al., 2004). Whether other organ clocks communicate with the kidney clocks remains unknown. Timing of food intake is another important external timing cue that can regulate the kidney clocks (Zhang et al., 2021). Whether this subsequently affects renal function rhythms remains unclear but a recent study in rats has shown that feeding of a high salt diet during the rest period caused loss of diurnal variation in renal sodium excretion (Rhoads et al, 2022). Changes in core temperature have also been shown to cause changes in the kidney clock rhythm (Ohnishi et al., 2014). Glucocorticoids have been suggested to regulate the kidney clocks. Glucocorticoids are secreted rhythmically from the adrenal gland in response to circadian and stress-related stimuli and contribute to regulation of many renal processes, including renal blood flow, glomerular filtration rate, and water and electrolyte metabolism (reviewed in Hunter et al., 2014). Disruption in glucocorticoid rhythm has implications on renal function and has been suggested to impact the clock. This has been shown by Ivy et al., where mice infused with glucocorticoids (corticosterone in rodents) at mid-physiological range with its rhythm attenuated caused altered kidney clock gene expression and blunting of the variation of the renal sodium chloride cotransporter (NCC) activity. Finally, the endothelin axis has been shown to alter the kidney clocks. Endothelin influences renal function, for example, via binding to endothelin A receptor to induce vasoconstriction in the renal vasculature but inhibiting sodium reabsorption in the collecting duct via endothelin B receptor (reviewed in Douma et al., 2021). In a study by Speed et al, high salt feeding for a week led to a 4 hour phase shift in the peak expression of a core clock gene called Bmal1 in the inner medulla (where there is high expression of the endothelin system). It is hypothesized that this phase shift is part of the natriuretic response. However, the ETB receptor deficient rat that has salt-sensitive blood pressure, high salt feeding did not lead to this phase shift in inner medullary Bmal1. Future studies are needed to better understand how light, food, temperature, and hormones affects the kidney clocks, and whether this influences renal function. The process of aging is associated with a reduction in diurnal variations in sleep/wake cycles, body temperature, and hormone secretions, so it is reasonable to hypothesize this could influence the kidney clocks and contribute to impaired renal function in aging (Figure 1).

Figure 1. Arising questions on the impact of aging on regulation of the kidney clocks and subsequent impact on renal function. Diagram created with Biorender, with permission.

 Recent research in this area has assessed  age-related changes in circadian transcriptional output (Ding et al., 2021; Wolff et al., 2022). In these studies, tissues, including kidney, hypothalamus, lung, skeletal muscle, heart, and adrenal gland, were collected from male C57B6/J mice aged 6 (young), 18 (aged), and 27 months (old). The tissues from the mice were collected every 4 hours for 48 hours in total darkness for RNAseq analysis. Mice were exposed to total dark conditions to study circadian gene expression under a free-running circadian state; intrinsic circadian rhythms that are not influenced by environmental time cues (in this case, light exposure). The circadian transcriptome was identified using the cosinor model (diffCircadian software, Ding et al., 2021), where circadian rhythmically expressed genes were defined as those with 24 hour cosine oscillations (based upon a raw p value of <0.01). Interestingly, the largest changes in rhythmically expressed genes were seen in the kidney with ~75% decline from young to old mice therefore, only 25% of rhythmically expressed genes remained rhythmic. This included attenuation of the rhythmic gene expression of several ion transporters, including the alpha subunit of the epithelial sodium channel and sodium/potassium ATPase alpha 1 subunit. Whether this contributes to dampened renal electrolyte rhythms and worsened kidney function seen in aging remains to be explored. The RNAseq data from the studies described above is available in the CircaAge database (Figure 2; Aging Circadian Database (shinyapps.io)) to provide the science community with the ability to search for their own genes of interest in these organs across circadian time and age. 

Figure 2. A circadian mRNA database across ages and tissues in male C57B6/J mice. Aging Circadian Database (shinyapps.io).

Overall, current research suggests that age-related alterations in circadian clock output should be considered a key process of aging that likely contributes to changes in cell and tissue homeostasis in the aged population. Understanding the relationship between the circadian system and the physiology of aging will offer opportunities to improve quality of life, promote healthy aging, and enhance treatment strategies.

 

 

Reviewed by: Elinor Mannon, Matthew Sparks, Kelly Hyndman

 

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Influence of Circadian Clock on Blood Pressure Control

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