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J. Biol. Chem., Vol. 278, Issue 15, 12605-12608, April 11, 2003
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From the Program in Matrix Biology, Divisions of Gastroenterology
and Nephrology, Department of Medicine and the Cancer Center, Beth
Israel Deaconess Medical Center and Harvard Medical School, Boston,
Massachusetts 02215, the ¶ Gene Expression Laboratory, Boystown
National Research Hospital, Omaha, Nebraska 68131, and the
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.
ACCELERATED PUBLICATION
Neutralization of Circulating Vascular Endothelial Growth Factor
(VEGF) by Anti-VEGF Antibodies and Soluble VEGF Receptor 1 (sFlt-1) Induces Proteinuria*
,§,,
, Department of Pediatric Oncology, Dana-Farber Cancer Institute
and Harvard Medical School, Boston, Massachusetts 02215
*
This work was supported in part by National Institutes of
Health (NIH) Grants DK-51711, DK 55001, by NIH renal Training Grant T32DK07199-25, and by research funds from the Program in Matrix Biology
at the Beth Israel Deaconess Medical Center.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to this work.
§
Supported by Japan Research Foundation for Clinical Pharmacology
between 2001 and 2002. Currently supported by Stop & Shop Family
Pediatric Brain Tumor Program.
**
To whom correspondence should be addressed: Harvard Medical School,
Director, Program in Matrix Biology, DANA 514, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston MA 02215. Tel.: 617-667-0445; Fax: 617-975-5663; E-mail:
rkalluri@bidmc. harvard.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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