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Sugimoto, H. et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J. Biol. Chem. 278, 12605-12608

Harvard University, Cambridge, Massachusetts, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 05/2003; 278(15):12605-8. DOI: 10.1074/jbc.C300012200
Source: PubMed

ABSTRACT There are about 2.5 million glomeruli in the kidneys each consisting of a barrel of glomerular basement membrane surrounded by glomerular endothelial cells on the inside and glomerular epithelial cells with established foot processes (podocytes) on the outside. Defects in this filtration apparatus lead to glomerular vascular leak or proteinuria. The role of vascular endothelial growth factor (VEGF) in the regulation of glomerular vascular permeability is still unclear. Recent studies indicate that patients receiving anti-VEGF antibody therapy may have an increased incidence of proteinuria. In a different setting, pregnancies complicated by preeclampsia are associated with elevated soluble VEGF receptor 1 protein (sFlt-1), endothelial cell dysfunction and proteinuria. These studies suggest that neutralization of physiologic levels of VEGF, a key endothelial survival factor, may lead to proteinuria. In the present study, we evaluated the potential of anti-VEGF neutralizing antibodies and sFlt-1 in the induction of proteinuria. Our studies demonstrate that anti-VEGF antibodies and sFlt-1 cause rapid glomerular endothelial cell detachment and hypertrophy, in association with down-regulation of nephrin, a key epithelial protein in the glomerular filtration apparatus. These studies suggest that down-regulation or neutralization of circulating VEGF may play an important role in the induction of proteinuria in various kidney diseases, some forms of cancer therapy and also in women with preeclampsia.

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    • "In pre - eclampsia , sFlt - 1 is elevated and has since been considered a marker for pre - eclampsia ( Vuorela et al . , 2000 ; Buhimschi et al . , 2005 ) . In Wt mice , neutralization of VEGF - induced proteinuria ( Sugimoto et al . , 2003 ) and sFlt - 1 gene transfer provoked pre - eclampsia - like signs ( Maynard et al . , 2003 ; Lu et al . , 2007 ) . Cudmore et al . ( 2007 ) showed that , in vitro , the overexpression of HO - 1 in endothelial cells by using a retrovirus - inhibited sFlt - 1 release , whereas HO - 1 inhibition potentiated sFlt - 1 production from endoth"
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    • "In addition, the crucial role of VEGF in microvascular complications of diabetes has been recently examined [Long et al. 2010]. Pharmacological and genetic disruptions of VEGF have been shown to result in significant proteinuria and glomerular endotheliosis [Eremina et al. 2003; Sugimoto et al. 2003]. VEGF is known to have a central role in angiogenesis, vascular homeostasis, and the maintenance of capillary integrity, particularly in the kidney glomerulus [Long et al. 2010]. "
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    • "Although this proteinuria was largely asymptomatic and low-grade, high-grade proteinuria and acute kidney injury have been described in some cases [6] [18]. There is a profound body of evidence that VEGF is important in maintaining glomerular endothelial cell health and healing [19] and that its absence induces proteinuria, release of procoagulant proteins, and glomerular endotheliosis [16] [20]. All these studies indicate that neutralization of circulating VEGF (either by sFlt-1 or antiangiogenetic drugs) may play an important role in the induction of proteinuria in cancer therapy and in women with preeclampsia. "
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