1,25-Dihydroxyvitamin D3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix.
OBJECTIVE
Whether treatment with vitamin D receptor activators contributes to cardiovascular disease in patients with chronic kidney disease is a matter of debate. We studied mechanisms involved in vitamin D-related vascular calcifications in vivo and in vitro.


METHODS
Aortic calcifications were induced in subtotally nephrectomized (SNX) rats by treatment with a high dose (0.25 μg/kg per day) of 1,25-dihydroxyvitamin D3 (calcitriol) given for 6 weeks. Likewise, primary rat vascular smooth muscle cells (VSMCs) were incubated with calcitriol at concentrations ranging from 10 to 10 mol/l. Immunohistochemistry revealed that the aortic expression of osteopontin, osteocalcin and bone sialoprotein was significantly increased in calcitriol-treated SNX rats compared to untreated SNX controls. In addition, aortic expression of the transient receptor potential vanilloid calcium channel 6 (TRPV6) and calbindin D9k was significantly up-regulated by treatment with calcitriol. Furthermore, calcitriol significantly increased expression of the osteogenic transcription factor osterix. In-vitro studies showed similar results, confirming that these effects could be attributed to treatment with calcitriol.


CONCLUSIONS
High-dose calcitriol treatment induces an osteoblastic phenotype in VSMC both in SNX rats and in vitro, associated with up-regulation of proteins regulating mineralization and calcium transport, and of the osteogenic transcription factor osterix.
Department of Pediatric Nephrology, Campus Virchow Klinikum, Berlin, Germany.
Hong
H
Zebger-Gong
Dominik
D
Müller
Michaela
M
Diercke
Dieter
D
Haffner
Berthold
B
Hocher
Steven
S
Verberckmoes
Sven
S
Schmidt
Patrick C
PC
D'Haese
Uwe
U
Querfeld
D000818:Animals; D001018:Aortic Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D064026:Calbindins; D002114:Calcinosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002117:Calcitriol / Q000008:administration & dosage / Q000009:adverse effects*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009392:Nephrectomy; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014511:Uremia / Q000150:complications* / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D064026:Calbindins; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; C493717:Runx2 protein, rat; D064030:S100 Calcium Binding Protein G; C576506:S100G protein, human; C576508:S100g protein, rat; C495181:Sp7 protein, rat; D050916:TRPV Cation Channels; C492241:TRPV5 protein, rat; C120776:TRPV6 channel; D014157:Transcription Factors; D002117:Calcitriol