Did you know that kidneys can tell time?
Don’t trash your watch just yet. This phenomenon involves relative time, not what the clock says. A number of nephro-centric body functions vary throughout the day. Blood pressure normally dips at night, and salt and water excretion also drop while we sleep. When the latter gets dysregulated, people must get up at night to pee (nocturnia in fancy doctor talk) and suffer from these sleep interruptions. Since such disruptions occur more as we age, these clock issues may contribute to increased cardiovascular disease risk.
How does our body clock get controlled? From a recent paper by Michelle Gumz, PhD, an Assistant Professor of medicine at Florida, comes the explanation of four proteins that control circadian rhythm:
The four core proteins are CLOCK, Bmal1, Period (Per 1-3), and Cryptochrome (Cry 1-2). CLOCK and Bmal1 heterodimerize and interact with E-box response elements to transcriptionally up-regulate circadian target genes, which include Per and Cry. Per and Cry interact and then repress the transcriptional activity of CLOCK and Bmal1 (5). In addition to transcriptional regulation, the circadian clock also undergoes post-translational modifications through the phosphorylation of the Per proteins by the circadian kinases Casein Kinase 1 isoforms δ/ε (CK1δ/ε). Phosphorylation by CK1δ/ε allows Per1 nuclear entry (6,7).
Dr. Gumz has two recent papers examining how the Period proteins regulate other systems in the kidney. Per1 regulates sodium transport in the distal convoluted tubule via transcription of sodium cotransporters. This can help explain why we normally decrease urine output overnight. Per1 also participates in regulation of the endothelin system, with results varying both by time of day and tissue. In addition to downstream effects of endothelin on salt and water transport that help explain other diurnal phenomena, these data may have important implications for the clinical use of endothelin receptor blockers. If peak activity in the organ of interest occurs in the day, then morning dosing may be most appropriate. If an organ active at night is the therapeutic target, bedtime dosing may be key.
I wonder how many other systems have circadian variation that could affect drug dosing? Only one way to find out, and that is to do the experiments.
Of course, the deeper question is why diurnal variation is so important. Health disparities for people doing weird shift work and those with sleep disturbances point toward the importance of our circadian cycles. All of this evidence that our body’s processes are regulated at the cellular level to promote sleep also tell us that this state is pretty damn important…even though we still do not really know why.