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The Soluble VEGF Receptor sFlt1 Contributes to Endothelial Dysfunction in CKD

Giovana S. Di Marco^*, Stefan Reuter^*, Uta Hillebrand^*,, Susanne Amler, Maximilian König^*, Etienne Larger, Hans Oberleithner, Eva Brand^*, Hermann Pavenstädt^* and Marcus Brand^*

*Department of Internal Medicine D,
Institute of Physiology, and
Department of Medical Informatics and Biomathematics, University Clinics Münster, Münster, Germany; and
INSERM 833, Collège de France, Paris, France

Correspondence: Dr. Marcus Brand, Department of Medicine D, University Clinics Münster, Albert-Schweitzer-Strasse 33, D 48149 Münster, Germany. Phone: +49-251-8347-539; Fax: +49-835-6973; E-mail: Brand.Marcus{at}ukmuenster.de

Received for publication January 16, 2009. Accepted for publication May 21, 2009.

Endothelial dysfunction contributes to the increased cardiovascular risk that accompanies CKD. We hypothesized that the soluble VEGF receptor 1 (sFlt-1), a VEGF antagonist, plays a role in endothelial dysfunction and decreased angiogenesis in CKD. We enrolled 130 patients with CKD stages 3 to 5 and 56 age- and gender-matched control patients. Plasma sFlt-1 levels were higher in patients with CKD and, after multivariate regression analyses, exclusively associated with renal function and levels of vWF, a marker of endothelial dysfunction. Compared with serum from control patients, both recombinant sFlt-1 and serum from patients with CKD had antiangiogenic activity in the chick chorioallantoic membrane (CAM) assay, induced endothelial cell apoptosis in vitro, and decreased nitric oxide generation in two different endothelial cell lines. Pretreating the sera with an antibody against sFlt-1 abrogated all of these effects. Furthermore, we observed increased sFlt1 levels in 5/6-nephrectomized rats compared with sham-operated animals. Finally, using real-time PCR and ELISA, we identified monocytes as a possible source of increased sFlt-1 in patients with CKD. Our findings show that excess sFlt-1 associates with endothelial dysfunction in CKD and suggest that increased sFlt-1 may predict cardiovascular risk in CKD.

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