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1 Unidad de Investigacion, Servicio de Nefrologia, Hospital Universitario Reina Sofia, Cordoba, Avda Menendez Pidal s/n, Spain
2 Dept. Biologia Ambiental y Salud Publica, Universidad de Huelva, Huelva, Avda. Fuerzas Armadas s/n, Spain
3 Dept. Medicina y Cirugia Animal, Universidad de Cordoba, Cordoba, Ctra. Madrid-Cadiz, Spain
4 Dept. Medicina y Cirugia Animal, Universidad de Huelva, Cordoba, Ctra. Madrid-Cadiz, Spain
5 Department of Metabolic Disorders, Amgen Inc, Thousand Oaks, California, United States
6 Unidad de Investigación, Servicio de Nefrologia, Hospital Universitario Reina Sofía, Cordoba, Spain
* To whom correspondence should be addressed. E-mail: pv1agtee{at}uco.es.
We have previously demonstrated that extracellular calcium regulates vitamin D receptor (VDR) expression by parathyroid cells. Since the calcimimetic R-568 potentiates the effects of calcium on the calcium-sensing receptor, it was hypothesized that administration of R-568 may result in increased VDR expression in parathyroid tissue. In vitro studies of the effect of R-568 on VDR mRNA and protein were conducted in cultures of whole rat parathyroid glands and human hyperplastic parathyroid glands. In vivo studies in Wistar rats examined the effect of R-568 and calcitriol alone and in combination. Incubation of rat parathyroid glands in vitro with R-568 (0.001 to 1 µM) resulted in a dose-dependent decrease in parathyroid hormone (PTH) secretion and an increase in mean ± SE VDR expression. Incubation in 1 mM calcium + 0.001 µM R-568 elicited an increase in VDR mRNA (306% ± 46%) similar to the maximum increase detected (1.5 mM calcium) (330% ± 42%). In vivo, VDR mRNA was increased after administration of either R-568 (168% ± 9%, P < 0.001 versus control) or calcitriol (198% ± 16%, P < 0.001 versus control). Treatment with R-568 also increased VDR protein in normal rat parathyroid glands and in human parathyroid glands with diffuse, but not nodular, hyperplasia. In conclusion, the present study shows that the calcimimetic R-568 exerts a stimulatory effect on VDR expression in the parathyroid glands of study models, and provides additional evidence for the use of calcimimetics in the treatment of secondary hyperparathyroidism.
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