title: Vascular Calcification Induced by Chronic Kidney Disease Is Mediated by an Increase of 1α-Hydroxylase Expression in Vascular Smooth Muscle Cells.
abstract: Vascular calcification (VC) is a complication of chronic kidney disease that predicts morbidity and mortality. Uremic serum promotes VC, but the mechanism involved is unknown. A role for 1,25(OH)2D3in VC has been proposed, but the mechanism is unclear because both low and high levels have been shown to increase it. In this work we investigate the role of 1,25(OH)2D3produced in vascular smooth muscle cells (VSMCs) in VC. Rats with subtotal nephrectomy and kidney recipient patients showed increased arterial expression of 1α-hydroxylase in vivo. VSMCs exposed in vitro to serum obtained from uremic rats also showed increased 1α-hydroxylase expression. Those increases were parallel to an increase in VC. After 6 days with high phosphate media, VSMCs overexpressing 1α-hydroxylase show significantly higher calcium content and RUNX2 expression than control cells. 1α-hydroxylase null mice (KO) with subtotal nephrectomy and treated with calcitriol (400 ng/kg) for 2 weeks showed significantly lower levels of vascular calcium content, Alizarin red staining, and RUNX2 expression than wild-type (WT) littermates. Serum calcium, phosphorus, blood urea nitrogen (BUN), PTH, and 1,25(OH)2D3levels were similar in both calcitriol-treated groups. In vitro, WT VSMCs treated with uremic serum also showed a significant increase in 1α-hydroxylase expression and higher calcification that was not observed in KO cells. We conclude that local activation of 1α-hydroxylase in the artery mediates VC observed in uremia. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Nephrology Research Department, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Torremadé
authors.affiliation: Nephrology Research Department, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Milica
authors.initials: M
authors.lastname: Bozic
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Panizo
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Barrio-Vazquez
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fernandez-Martín
authors.affiliation: Oncogenic Signaling and Development group. IRBLleida, University of Lleida, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Encinas
authors.affiliation: Calcium Research Laboratory, McGill University Health Center and Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: Nephrology Research Department, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Arcidiacono
authors.affiliation: Nephrology Research Department, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Fernandez
authors.affiliation: Nephrology Research Department, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain. valdivielso@medicina.udl.es.
authors.forename: José M
authors.initials: JM
authors.lastname: Valdivielso
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D061205:Vascular Calcification / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology
chemical_list: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human
keywords: CARDIOVASCULAR DISEASE; CHRONIC KIDNEY DISEASE; MINERAL METABOLISM; UREMIC TOXINS; VITAMIN D