Abstract
Circadian clocks in mammals function in most organs and tissues throughout the body. Various renal functions such as the glomerular filtration and excretion of electrolytes exhibit circadian rhythms. Although it has been reported that the expression of the clock genes composing molecular oscillators show apparent daily rhythms in rodent kidneys, functional variations of regional clocks are not yet fully understood. In this study, using macroscopic bioluminescence imaging method of the PER2::Luciferase knock-in mouse kidney, we reveal that strong and robust circadian clock oscillation is observed in the medulla. In addition, the osmotic pressure in the inner medulla shows apparent daily fluctuation, but not in the cortex. Quantitative-PCR analysis of the genes contributing to the generation of high osmotic pressure or the water re-absorption in the inner medulla, such as vasopressin receptors (V1aR, V2R), urea transporter (UT-A2) and water channel (Aqp2) show diurnal variations as well as clock genes. Deficiency of an essential clock gene Bmal1 impairs day-night variations of osmotic pressure gradient in the inner medulla, suggesting that circadian clocks in the medulla part of the kidney may regulate the circadian rhythm of cortico-medullary osmotic pressure gradient, and may contribute physiological day-night rhythm of urination.
Highlights
In mammals, various physiological aspects, sleep/awake cycles, and energy metabolisms, cardiovascular functions and renal functions exhibit the apparent daily fluctuation[1,2,3,4]
By high-sensitivity charge-coupled device (CCD) camera-based macroscopic imaging systems with PERIOD2::LUCIFERASE (PER2::Luc) knock-in mouse which express firefly luciferase fused PER2 protein[11], we studied the localization of the PER2::Luc activity in the kidney (Fig. 1a–c)
We revealed the tissue-autonomous circadian clock oscillation in cultured kidneys using bioluminescence macroscopic imaging devices
Summary
Various physiological aspects, sleep/awake cycles, and energy metabolisms, cardiovascular functions and renal functions exhibit the apparent daily fluctuation[1,2,3,4]. Molecular clock passes rhythmic expression patterns to the clock-controlled output genes (CCGs) that link the oscillator to clock controlled physiological processes via transcriptional regulations[9]. Renal excretion of urea and water, and electrolyte levels in urine including Na and K follow circadian patterns[4, 25,26,27]. Nikolaeva et al performed comprehensive gene expression analysis and found that 277 transcripts showed circadian oscillation in kidneys, whereas the cycling transcripts decreased to 174 in Clock mutant mice[26]. It has been reported that the expression of clock genes showed apparent daily rhythms, functional variations of regional clocks in the kidney have not yet been fully understood. We examined day-night variations of cortico-medullary osmotic pressure gradient in Bmal[1] deficient mouse kidneys
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