title: Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes.
abstract: Vascular endothelial growth factor (VEGF) is a cytokine that potently stimulates angiogenesis, microvascular hyperpermeability, and endothelium-dependent vasodilation, effects that are largely mediated by endothelial nitric oxide synthase (eNOS). The expression of VEGF is pronounced in glomerular visceral epithelial cells, but its function in renal physiology and pathophysiology is unknown. VEGF expression is upregulated by high ambient glucose concentrations in several cell types in vitro and in glomeruli of diabetic rats. To assess the role of VEGF in the pathophysiology of early renal dysfunction in diabetes, monoclonal anti-VEGF antibodies (Ab) were administered to control and streptozotocin-induced diabetic rats for 6 wk after induction of diabetes. Based on in vitro binding studies, an adequate serum VEGF inhibitory activity was achieved during the entire course of anti-VEGF Ab administration. Anti-VEGF Ab treatment but not administration of isotype-matched control Ab decreased hyperfiltration, albuminuria, and glomerular hypertrophy in diabetic rats. VEGF blockade also prevented the upregulation of eNOS expression in glomerular capillary endothelial cells of diabetic rats. Antagonism of VEGF had no effect on GFR and glomerular volume in control rats. These results identify VEGF as a pathogenetic link between hyperglycemia and early renal dysfunction in diabetes. Targeting VEGF may prove useful as a therapeutic strategy for the treatment of early diabetic nephropathy.
authors.affiliation: Renal Unit, Ghent University, Belgium.
authors.forename: An S DE
authors.initials: AS
authors.lastname: Vriese
authors.affiliation: Departments of Cell Biology and Pharmacology, Texas Biotechnology Corporation, Houston, Texas.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tilton
authors.affiliation: Institute of Anatomy and Cell Biology I, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marlies
authors.initials: M
authors.lastname: Elger
authors.affiliation: Departments of Cell Biology and Pharmacology, Texas Biotechnology Corporation, Houston, Texas.
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Stephan
authors.affiliation: Institute of Anatomy and Cell Biology I, University of Heidelberg, Heidelberg, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Kriz
authors.affiliation: Renal Unit, Ghent University, Belgium.
authors.forename: Norbert H
authors.initials: NH
authors.lastname: Lameire
mesh_terms: D000419:Albuminuria / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology / Q000628:therapy; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000628:therapy*; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000502:physiology; D005260:Female; D007678:Kidney Glomerulus / Q000503:physiopathology; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat