VEGF receptor 2 blockade leads to renal cyst formation in mice.
Polycystic kidney disease (PKD) is associated with mutations in PKD1 and PKD2 and vascular abnormalities. The links between the epithelial and vascular defects, however, are poorly understood. Vascular endothelial growth factor (VEGF) has been shown to be critical for normal kidney development. In animal models, blockade of VEGF in the perinatal period can lead to abnormal glomerular development, impaired nephrogenesis, proteinuria, and renal failure. We hypothesized that brief blockade of VEGF signaling during early postnatal kidney development can lead to renal cyst development. On days 2 and 4 of life, CD-1 mice were treated with antibodies generated against the extracellular portion of the VEGF receptor 2 (DC101), the area of the receptor where VEGF binding occurs. Mice developed renal cysts between 2 and 3 weeks. The DC101-treated mice also had increased cell proliferation in the renal tubule epithelium. In addition, mice receiving DC101 developed abnormal glomeruli, proteinuria, and patchy cellular infiltrates. Early disruption of VEGFR-2 signaling during the perinatal period results in renal cyst formation, impaired glomerulogenesis, and inflammation. VEGF could be a key link between vascular and cystic changes in kidney cyst formation.
Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland 21287, USA. smorrow@jhmi.edu
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McGrath-Morrow
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Cho
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Molls
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Burne-Taney
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Haas
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Hicklin
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Tuder
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Rabb
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D007150:Immunohistochemistry; D052177:Kidney Diseases, Cystic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; C511761:DC101 monoclonal antibody; D040301:Vascular Endothelial Growth Factor Receptor-2