Circadian rhythms of mineral metabolism in chronic kidney disease-mineral bone disorder

Abstract

Purpose of review: The circadian rhythms have a systemic impact on all aspects of physiology. Kidney diseases are associated with extremely high-cardiovascular mortality, related to chronic kidney disease-mineral bone disorder (CKD-MBD), involving bone, parathyroids and vascular calcification. Disruption of circadian rhythms may cause serious health problems, contributing to development of cardiovascular diseases, metabolic syndrome, cancer, organ fibrosis, osteopenia and aging. Evidence of disturbed circadian rhythms in CKD-MBD parameters and organs involved is emerging and will be discussed in this review.

Recent findings: Kidney injury induces unstable behavioral circadian rhythm. Potentially, uremic toxins may affect the master-pacemaker of circadian rhythm in hypothalamus. In CKD disturbances in the circadian rhythms of CKD-MBD plasma-parameters, activin A, fibroblast growth factor 23, parathyroid hormone, phosphate have been demonstrated. A molecular circadian clock is also expressed in peripheral tissues, involved in CKD-MBD; vasculature, parathyroids and bone. Expression of the core circadian clock genes in the different tissues is disrupted in CKD-MBD.

Summary: Disturbed circadian rhythms is a novel feature of CKD-MBD. There is a need to establish which specific input determines the phase of the local molecular clock and to characterize its regulation and deregulation in tissues involved in CKD-MBD. Finally, it is important to establish what are the implications for treatment including the potential applications for chronotherapy.

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FIGURE 1

The molecular circadian clock. The transcription factors, circadian locomotor output cycles kaput (CLOCK) and brain-muscle Arnt-like protein 1 (BMAL1), are major components of the molecular circadian clock positive limb. CLOCK and BMAL1 heterodimerize, bind to E-box elements in the promoters of period (PER) and cryptochrome (CRY) and drive the negative limb in the feedback loop. PER and CRY proteins translocate back into the nucleus, hindering CLOCK and BMAL1 transcriptional activity, resulting in oscillation of the gene expressions in a circadian manner. This main loop is interplaying with a feedback loop driven by Rev-erb and receptor tyrosine kinase-like orphan receptor (ROR) mediating opposing actions, repressing or activating BMAL1 gene expression. The molecular circadian clock drives the expression of the clock-controlled tissue specific output genes and hereby about 10% of the transcriptome show circadian rhythmicity.

FIGURE 2

A simplified model of disturbed circadian rhythm in chronic kidney disease–mineral bone disorder. The circadian system involves the environmental cues that entrain the central pacemaker, a molecular circadian clock, located in the suprachiasmatic nucleus (SCN) and peripheral molecular circadian clocks, located in the peripheral cells, but being under control of the central pacemaker via neurohumoral signals. The kidney provides feedback input to the central clock as well. In chronic kidney disease the clock in central nervous system is potentially deregulated by uremic toxins, feedback input from the injured kidney as well as by disturbed response to environmental cues. The molecular clocks in organs involved in chronic kidney disease–mineral bone disorder are desynchronized from the central clock. The expressions of the peripheral clock genes in the parathyroid gland, vasculature, bone and kidney are disturbed, contributing to the chronic kidney disease–mineral bone disorder symptoms of secondary hyperparathyroidism, vascular calcifications, renal osteodystrophy, kidney fibrosis and disturbed circadian rhythmicity of the plasma parameters related to chronic kidney disease–mineral bone disorder, activin A, fibroblast growth factor 23, parathyroid hormone and phosphate.

FIGURE 3

Disturbed circadian rhythms of chronic kidney disease–mineral bone disorder parameters in uremia. Circadian rhythms of circulating levels of plasma parathyroid hormone, fibroblast growth factor 23, phosphate, and activin A in chronic kidney disease and age-matched normal control rats are shown. Wistar rats were allocated to control or chronic kidney disease (5/6 nephrectomy and high phosphate diet for 24 weeks). Control rats exhibited circadian rhythm of all parameters. Significant rhythmicity was confirmed by cosinor analysis: parathyroid hormone (P < 0.0001), fibroblast growth factor 23 (P < 0.05), phosphate (P < 0.0001) and activin A (P < 0.01). Chronic kidney disease completely obliterated the circadian rhythm of parathyroid hormone and activin A. The circadian rhythms of fibroblast growth factor 23 and phosphate were maintained in chronic kidney disease rats (fibroblast growth factor 23: P < 0.05, phosphate: P < 0.0001), however, both rhythms were severely disturbed. As such, the acrophase of fibroblast growth factor 23 shifted from 13:00 in control to 09:00 in chronic kidney disease rats, whereas the acrophase of phosphate shifted from 16:00 in controls to 00:00 in chronic kidney disease rats [12^▪].

FIGURE 4

Circadian rhythm of plasma activin A and phosphate in normal and uremic rats on different phosphate diets. Induction and secretion of activin A from the injured kidney. Plasma activin A exhibits circadian rhythmicity in control rats, whereas the rhythm is obliterated by chronic kidney disease. An increase in plasma activin A levels was observed in chronic kidney disease rats, but depending upon the time of the day. In chronic kidney disease rats on a low phosphate diet the increase in plasma activin A was inhibited. However, the circadian rhythm was not restored (a). Similarly, circadian rhythmicity of plasma phosphate was disturbed in chronic kidney disease rats. Furthermore, chronic kidney disease rats on a high phosphate diet developed hyperphosphatemia. This was prevented by the low phosphate diet, which however did not restore the circadian rhythmicity of plasma phosphate in chronic kidney disease (b) [12^▪]. Kidney injury was induced by unilateral ureter obstruction for 15 days and blood sampling from the isolated renal artery and vein was performed. Activin A was induced and secreted of from the injured kidney (c). partly nephrectomized: 5/6 partial nephrectomy. HP, high-phosphate diet; LP, low-phosphate diet; SP, standard-phosphate diet. Mean ± SEM.