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Submaximal suppression of parathyroid hormone ameliorates calcitriol-induced aortic calcification and remodeling and myocardial fibrosis in uremic rats

Jung, Susanne; Querfeld, Uwe; Müller, Dominik; Rudolph, Birgit; Peters, Harm; Krämer, Stephanie

doi: 10.1097/HJH.0b013e328357c049
ORIGINAL PAPERS: Kidney
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Background and objective: In subtotally nephrectomized rats, we studied to what extent high-dose calcitriol-induced cardiovascular disease can be modulated by almost complete suppression of parathyroid hormone (PTH), mediated by either cinacalcet (CINA) or parathyroidectomy (PTX).

Methods: Five groups were studied: sham-operated controls, uremic (U), uremic with calcitriol (U+1,25D), uremic and calcitriol with CINA (U+1,25D+CINA) and uremic and calcitriol with PTX (U+1,25D+PTX). Treatments lasted 14 weeks.

Results: Compared with U group animals, PTH was significantly lower with calcitriol treatment and almost completely suppressed in animals treated with either PTX or CINA. Serum calcium and phosphorus levels were similarly elevated in all groups receiving calcitriol. Renal function in uremic animals was significantly more impaired in the U+1,25D group. Aortic calcifications were pronounced in U+1,25D animals and reduced by more than 50% by concomittant treatment with CINA or PTX. Chondrocytes were observed near areas of calcification (>90%) and endochondral bone formation was confirmed by positive immunofluorescence for chondrocytic transcription factor sox9 and matrix protein collagen X. Altered arterial (aneurysmatic) geometry with a significant increase in wall/lumen and lumen/body weight ratio was found only in the U+1,25D group. Myocardial fibrosis was present in all uremic groups with a significant increase in the U+1,25D group. Connective tissue growth factor messenger RNA was significantly upregulated only in the U+1,25D group.

Conclusion: Submaximal suppression of PTH by either CINA or PTX reduced vascular calcifications, arterial remodeling and myocardial fibrosis to a similar degree and independent of the serum calcium and phosphorus levels. These data do not indicate vasculotropic effects of calcimimetics independent of PTH suppression.

aCenter for Cardiovascular Research

bDepartment of Pediatric Nephrology

cInstitute of Pathology

dDepartment of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany

Correspondence to Professor Dr Uwe Querfeld, Department of Pediatric Nephrology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. Tel: +49 30 450516012; fax: +49 30 450516912; e-mail: uwe.querfeld@charite.de

Abbreviations: CINA, cinacalcet; CKD, chronic kidney disease; CVD, cardiovascular disease; PTH, parathyroid hormone; PTX, parathyroidectomy; SNX, subtotal nephrectomy; VDRA, vitamin D receptor activator

Received 7 September, 2011

Revised 23 June, 2012

Accepted 4 July, 2012

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.