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Fetuin-A Protects against Atherosclerotic Calcification in CKD

Ralf Westenfeld^*, Cora Schäfer, Thilo Krüger^*, Christian Haarmann^*, Leon J. Schurgers, Chris Reutelingsperger, Ognen Ivanovski, Tilman Drueke, Ziad A. Massy^||, Markus Ketteler^¶, Jürgen Floege^* and Willi Jahnen-Dechent

Departments of ^* Nephrology and Biomedical Engineering, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Aachen, and ^¶ Department of Nephrology, Klinikum Coburg GmbH, Coburg, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands; and INSERM Unit 845, Necker Hospital, Paris, and ^|| Inserm ERI-12 and University of Picardie Jules Verne and Amiens University Hospital, Amiens, France

Correspondence: Dr. Willi Jahnen-Dechent, Department of Biomedical Engineering, Biointerface Group, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany. Phone: +49-241-80-80163; Fax: +49-241-80-82573; E-mail: willi.jahnen{at}rwth-aachen.de

Received for publication June 5, 2008. Accepted for publication January 19, 2009.

Reduced serum levels of the calcification inhibitor fetuin-A associate with increased cardiovascular mortality in dialysis patients. Fetuin-A–deficient mice display calcification of various tissues but notably not of the vasculature. This absence of vascular calcification may result from the protection of an intact endothelium, which becomes severely compromised in the setting of atherosclerosis. To test this hypothesis, we generated fetuin-A/apolipoprotein E (ApoE)-deficient mice and compared them with ApoE-deficient and wild-type mice with regard to atheroma formation and extraosseous calcification. We assigned mice to three treatment groups for 9 wk: (1) Standard diet, (2) high-phosphate diet, or (3) unilateral nephrectomy (causing chronic kidney disease [CKD]) plus high-phosphate diet. Serum urea, phosphate, and parathyroid hormone levels were similar in all genotypes after the interventions. Fetuin-A deficiency did not affect the extent of aortic lipid deposition, neointima formation, and coronary sclerosis observed with ApoE deficiency, but the combination of fetuin-A deficiency, hyperphosphatemia, and CKD led to a 15-fold increase in vascular calcification in this model of atherosclerosis. Fetuin-A deficiency almost exclusively promoted intimal rather than medial calcification of atheromatous lesions. High-phosphate diet and CKD also led to an increase in valvular calcification and aorta-associated apoptosis, with wild-type mice having the least, ApoE-deficient mice intermediate, and fetuin-A/ApoE-deficient mice the most. In addition, the combination of fetuin-A deficiency, high-phosphate diet, and CKD in ApoE-deficient mice greatly enhanced myocardial calcification, whereas the absence of fetuin-A did not affect the incidence of renal calcification. In conclusion, fetuin-A inhibits pathologic calcification in both the soft tissue and vasculature, even in the setting of atherosclerosis.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673