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Abstract: TH-OR14

Circadian PTH Secretion Is Entrained by Feeding, While the Internal Circadian Parathyroid Clock Is Independent but Affected by CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Egstrand, Søren, Dept. of Nephrology, Herlev Hospital, Copenhagen, Denmark
  • Nordholm, Anders, Dept. of Nephrology, Herlev Hospital, Copenhagen, Denmark
  • Mace, Maria Lerche, Dept. of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • Morevati, Marya, Dept. of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • Olgaard, Klaus, Dept. of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • Lewin, Ewa, Dept. of Nephrology, Herlev Hospital, Copenhagen, Denmark
Background

We have previously shown that an internal molecular circadian clock operates in the parathyroids. Whether this circadian clock regulates the 24h rhythm of PTH secretion and whether it is impacted by feeding or CKD is unknown.

Methods

Rats were kept in 12h:12h light:dark cycle and fed ad libitum. Blood samples and parathyroid glands were harvested at 4h interval (N=38). Then feeding was restricted to the inactive light phase at ZT2-ZT12 (ZT: zeitgebertime, time since lights on) for 4 weeks and blood and glands obtained again (N=39). CKD was induced by 5/6 nephrectomy and high phosphate (P) diet for 8 weeks and parathyroid glands were harvested every 4th-hour (N=44). Plasma PTH, P, total calcium, FGF23, and urea were measured. Parathyroid expression of core circadian clock genes was examined by qPCR.

Results

Circadian rhythmicity was found for PTH (p<0.0002), P (p<0.0001), FGF23 (p<0.02), and urea (p<0.0001). Restricted feeding to the habitual inactive period inverted the acrophase timing of PTH (ZT9.6 → ZT23.6), P (ZT8.7 → ZT21), FGF23 (ZT7.4 → ZT22.9) and urea (ZT21.2 → ZT8.4). Restricted feeding did not significantly affect the period, acrophase timing, MESOR or amplitude of circadian clock genes: Bmal1, Per1-3, Cry1-2 and Rev-erbα.
The rhythmicity of parathyroid circadian clock genes was severely deregulated in CKD with significant upregulated MESOR of Per1 (p<0.0002), Per2 (p<0.03), and Rev-erbα (p<0.004) and downregulation of Npas2 (p<0.05). The significant rhythmicity of Per1 (p<0.02) was abolished. In CKD the best fitting period of rhythmicity was reduced to 20h as opposed to the normal 24h for Per1, Per2, Per3 and Cry2. Significant shifts in acrophase were found for Npas2, Per3 and Cry1, while amplitude of Rev-erbα increased.

Conclusion

Feeding restricted to the inactive period inverted the acrophase of plasma PTH, P and FGF23 and revealed a clear dissociation between the phase of PTH secretion rhythm and the phase of the circadian clock in the parathyroid glands. In CKD the circadian rhythm of core clock genes were significantly interfered, affecting MESOR, phase, period, amplitude as well as rhythmicity.