Kidney Circadian Clock Affects Metabolic Processes, Drug Pharmacokinetics

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Many of the body’s processes follow a natural daily rhythm, or circadian clock, that is based on regular light-dark cycles that correspond to day and night. A circadian clock in the kidneys plays an important role in maintaining balance throughout the body, and alterations to the clock can influence metabolism in both health and disease. For example, in individuals who take medications, the kidney’s circadian clock may control the process of drug elimination and therefore influence the duration of a drug’s action and the effectiveness of the therapy. The findings are published in the Journal of the American Society of Nephrology (Nikolaeva S et al. J Am Soc Nephrol. 2016 Apr 7. pii: ASN.2015091055).

The body’s circadian clock can have a range of influences, from determining when a person experiences peak cognitive performance to the timing of acute medical events such as strokes and heart attacks. The clock even enables maximum expression of genes at appropriate times of the day, allowing individuals to adapt to the earth’s rotation. Research has also shown that it can change as people age, so, for example, the brain signals the body to sleep earlier in the evening and to awaken earlier in the morning.

In the kidneys, physiologic processes such as sodium reabsorption, renal blood flow, and glomerular filtration follow a daily rhythm, and coordination of the timing of these processes allows the kidney to anticipate changes in metabolic and physiological demands throughout a 24-hour cycle. Results from animal and human studies indicate that circadian disruption and sleep deprivation can have detrimental effects on the kidneys.

In the JASN study, a team led by Dmitri Firsov, PhD, and Natsuko Tokonami, PhD, of the Department of Pharmacology and Toxicology at the University of Lausanne in Switzerland, blocked kidney cells’ expression of Bmal1, a gene critically involved in the circadian clock system, and found that the clock is responsible for the temporal adaptation of kidney function to the light and dark phases of the day that correspond to activity and rest.

“Since urine formation and excretion by the kidney is one of the most easily detectable rhythmic processes—we are forming and excreting much more urine during the day—we had hypothesized that at least a part of this rhythmicity is dependent on the circadian clock mechanism,” Tokonami said.

The researchers also performed experiments that combined functional, transcriptomic, and metabolomic analyses in mice with inducible conditional knockout of BMAL1 (the mouse version of Bmal1) in renal tubular cells. Blocking BMAL1 in adult mice did not produce obvious abnormalities in sodium, potassium, or water handling in the kidneys, but there were significant changes in the expression of genes related to metabolic pathways. Furthermore, kidneys from knockout mice exhibited changes indicative of altered mitochondrial function, an effect that could have a range of impacts on diverse functions within cells. The animals’ blood also contained altered levels of various amino acids, lipids, and other components, with significant increases in plasma urea and creatinine. The investigators’ partial analysis covered less than 5% of the total number of metabolites found in plasma, but even this restricted approach identified more than 50 metabolites that are differentially represented in the plasma of knockout mice.

The investigators noted that the animals’ kidneys had a reduced capacity to secrete the diuretic furosemide, paralleled by an approximate 80% decrease in expression of SLC22a8, a member of the organic anion transporter family of proteins that is known to mediate the excretion of many drugs.

“We’ve shown that the circadian clock in the kidney plays an important role in different metabolic and homeostatic processes at both the intrarenal and systemic levels and is involved in drug disposition,” Firsov said. The findings related to SLC22a8 suggest that by controlling the process of drug elimination, the kidney’s circadian clock may control how long a drug remains active, and therefore its effectiveness.

“In normal light-dark conditions and on a normal diet, these kidney-specific conditional Bmal1 knockout mice exhibit an intriguing phenotype that includes dramatic changes in gene expression affecting, among other things, pharmacokinetic pathways,” said Michelle Gumz, PhD, who was not involved with the research and is an Assistant Professor in the Division of Nephrology, Hypertension and Renal Transplantation within the University of Florida’s Department of Medicine. Her laboratory is investigating the role of the circadian clock in the kidney, with a focus on sodium transport regulation. “These findings have important implications for our understanding of how chronotherapy may affect renal function and drug efficacy. It will be very interesting to determine the effect of a modified diet or light cycle on fluid and electrolyte handling in this novel knockout mouse model.”