title: Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria.
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.
authors.affiliation: Program in Matrix Biology, Division of Gastroenterology, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hamano
authors.forename: David
authors.initials: D
authors.lastname: Charytan
authors.forename: Dominic
authors.initials: D
authors.lastname: Cosgrove
authors.forename: Mark
authors.initials: M
authors.lastname: Kieran
authors.forename: Akulapalli
authors.initials: A
authors.lastname: Sudhakar
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D000906:Antibodies; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000276:immunology / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000276:immunology / Q000502:physiology; D007678:Kidney Glomerulus / Q000502:physiology* / Q000503:physiopathology; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000276:immunology / Q000502:physiology; D051379:Mice; D011507:Proteinuria / Q000209:etiology*; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D042442:Vascular Endothelial Growth Factors
chemical_list: D000906:Antibodies; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040281:Vascular Endothelial Growth Factor Receptor-1