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Am J Physiol Endocrinol Metab. 2014 Dec 15;307(12):E1085-96. doi: 10.1152/ajpendo.00156.2014. Epub 2014 Oct 21.

The active form of vitamin D, calcitriol, induces a complex dual upregulation of endothelin and nitric oxide in cultured endothelial cells.

Author information

1
Research Unit and Nephrology Section, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain;
2
IBRLleida, Hospital Universitario Arnau de Vilanova, Lérida, Spain;
3
Research Unit and.
4
Servicio de Metabolismo Mineral y Óseo, Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain; Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain; and.
5
Physiology Department, Universidad de Alcalá, Madrid, Spain.
6
Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain; and Physiology Department, Universidad de Alcalá, Madrid, Spain.
7
Research Unit and Nephrology Section, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain; Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain; and.
8
Research Unit and Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain; and slorgil@salud.madrid.org.

Abstract

Despite the presence of vitamin D receptor (VDR) in endothelial cells, the effect of vitamin D on endothelial function is unknown. An unbalanced production of vasoactive endothelial factors such as nitric oxide (NO) or endothelin-1 (ET-1) results in endothelial dysfunction, which can alter the normal cardiovascular function. Present experiments were devoted to assess the effect of active vitamin D (calcitriol) on the synthesis of endothelial vasoactive factors. The results were that, in cells, calcitriol increased ET-1 and NO productions, which were measured by ELISA and fluorimetric assay, respectively. Calcitriol also increased endothelin-converting enzyme-1 (ECE-1) and endothelial-nitric oxide synthase (eNOS) activities, their mRNA (qPCR), their protein expressions (Western-blot), and their promoter activities (transfection assays). Calcitriol did not change prepro-ET-1 mRNA. The effect was specific to VDR activation because when VDR was silenced by siRNA, the observed effects disappeared. Mechanisms involved in each upregulation differed. ECE-1 upregulation depended on AP-1 activation, whereas eNOS upregulation depended directly on VDR activation. To evaluate the in vivo consequences of acute calcitriol treatment, normal Wistar rats were treated with a single ip injection of 400 ng/kg calcitriol and euthanized 24 h later. Results confirmed those observed in cells, that production and expression of both factors were increased by calcitriol. Besides, calcitriol-treated rats showed a slight rise in mean blood pressure, which decreased when pretreated with FR-901533, an ECE-1 antagonist. We conclude that calcitriol increases the synthesis of both ET-1 and NO in endothelial cells. However, the ET-1 upregulation seems to be biologically more relevant, as animals acutely treated with calcitriol show slight increases in blood pressure.

KEYWORDS:

endothelin-1; endothelium; nitric oxide; vitamin D

PMID:
25336523
DOI:
10.1152/ajpendo.00156.2014
[Indexed for MEDLINE]
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