Vitamin D receptor agonist VS-105 directly modulates parathyroid hormone expression in human parathyroid cells and in 5/6 nephrectomized rats.

Abstract

Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to treat secondary hyperparathyroidism (SHPT) associated with chronic kidney disease (CKD). Current VDRA therapy often causes hypercalcemia, which is a critical risk for vascular calcification. Previously we have shown that a novel VDRA, VS-105, effectively suppresses serum parathyroid hormone (PTH) without affecting serum calcium levels in 5/6 nephrectomized (NX) uremic rats. However, it is not known whether VS-105 directly regulates PTH gene expression. To study the direct effect of VS-105 on modulating PTH, we tested VS-105 and paricalcitol in the spheroid culture of parathyroid cells from human SHPT patients, and examined the time-dependent effect of the compounds on regulating serum PTH in 5/6 NX uremic rats (i.p. 3x/week for 14days). In human parathyroid cells, VS-105 (100nM) down-regulated PTH mRNA expression (to 3.6% of control) and reduced secreted PTH (to 43.9% of control); paricalcitol was less effective. VS-105 effectively up-regulated the expression of VDR (1.9-fold of control) and CaSR (1.8-fold of control) in spheroids; paricalcitol was also less effective. In 5/6 NX rats, one single dose of 0.05-0.2μg/kg of VS-105 or 0.02-0.04μg/kg of paricalcitol effectively reduced serum PTH by >40% on Day 2. Serum PTH remained suppressed during the dosing period, but tended to rebound in the paricalcitol groups. These data indicate that VS-105 exerts a rapid effect on suppressing serum PTH, directly down-regulates the PTH gene, and modulates PTH, VDR and CaSR gene expression more effectively than paricalcitol.

• Authors: Kaichiro Sawada, J Ruth Wu-Wong, Yung-Wu Chen, Jerry L Wessale, Genta Kanai, Takatoshi Kakuta, Masafumi Fukagawa
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 167 Pg. 48-54 (03 2017) ISSN: 1879-1220 [Electronic] England
• PMID: 27989797 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• 5-(2-(1-(1-(3-hydroxy-2,3-dimethylbutoxy)ethyl)-7alpha-methyldihydro-1H-inden-4(2H,5H,6H,7H,7alphaH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol
• Ergocalciferols
• Parathyroid Hormone
• RNA, Messenger
• Receptors, Calcitriol
• paricalcitol
• Calcitriol

Topics

• Animals
• Calcitriol (analogs & derivatives, chemistry)
• Down-Regulation
• Ergocalciferols (chemistry)
• Kidney (metabolism)
• Male
• Nephrectomy
• Parathyroid Glands (cytology, metabolism)
• Parathyroid Hormone (blood)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Calcitriol (agonists, metabolism)
• Spheroids, Cellular (metabolism)