Vascular endothelial growth factor is essential for hyperglycemia-induced structural and functional alterations of the peritoneal membrane

• Published in: Journal of the American Society of Nephrology Vol. 12; no. 8; pp. 1734 - 1741
• Main Authors: DE VRIESE, An S, TILTON, Ronald G, STEPHAN, Clifford C, LAMEIRE, Norbert H
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-08-2001
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Biological Transport; Blood Vessels - pathology; Capillary Permeability; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - pathology; Emergency and intensive care: renal failure. Dialysis management; Endothelial Growth Factors - antagonists & inhibitors; Endothelial Growth Factors - immunology; Endothelial Growth Factors - physiology; Female; Fluorescein-5-isothiocyanate - pharmacokinetics; Hyperglycemia - physiopathology; Intensive care medicine; Lymphokines - antagonists & inhibitors; Lymphokines - immunology; Lymphokines - physiology; Medical sciences; Microcirculation; Peritoneal Dialysis; Peritoneum - blood supply; Peritoneum - metabolism; Rats; Rats, Wistar; Reference Values; Serum Albumin - pharmacokinetics; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Kidney disease; Urinary system disease; Pathophysiology; Rat; Rodentia; Peritoneal dialysis; Extrarenal dialysis; Vertebrata; Chronic; Hyperglycemia; Mammalia; Vascular endothelium growth factor; Treatment; Animal; Renal failure; Complication
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.v1281734

Long-term peritoneal dialysis is associated with the development of functional and structural alterations of the peritoneal membrane. Long-term exposure to the high glucose concentrations in conventional peritoneal dialysate has been implicated in the pathogenesis of peritoneal hyperpermeability and neoangiogenesis. Vascular endothelial growth factor (VEGF) is an endothelial-specific growth factor that potently stimulates microvascular permeability and proliferation. High glucose exposure upregulates VEGF expression in various cell types and tissues. This study investigated whether VEGF plays a pathogenetic role in hyperglycemia-induced microvascular dysfunction in the peritoneal membrane. The peritoneal microcirculation of streptozotocin-induced diabetic rats and age-matched controls was studied in vivo with a combination of functional and morphologic techniques. The diabetic microcirculation was characterized by an elevated transport of small solutes, indicating the presence of an increased effective vascular surface area. The leakage of FITC-albumin was more rapid in diabetic vessels, suggesting hyperpermeability for macromolecules. Structurally, an increased vascular density with focal areas of irregular capillary budding was found in the diabetic peritoneum. The hyperglycemia-induced structural and functional microvascular alterations were prevented by long-term treatment with neutralizing anti-VEGF monoclonal antibodies, whereas treatment with isotype-matched control antibodies had no effect. VEGF blockade did not influence microvascular density or macromolecular leakage in control rats, demonstrating specificity for the hyperglycemia-induced alterations. The present results thus support an causative link among high glucose exposure, upregulation of VEGF, and peritoneal microvascular dysfunction.