title: Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease.
abstract: We sought to examine the pathogenic role of excessive VEGF-A expression in podocytes, since it has been reported that diabetic nephropathy and other glomerular diseases are associated with increased VEGF-A expression. The induction of podocyte-specific VEGF164 overexpression in adult transgenic mice led to proteinuria, glomerulomegaly, glomerular basement membrane thickening, mesangial expansion, loss of slit diaphragms, and podocyte effacement. When doxycycline-mediated VEGF164 was stopped, these abnormalities reversed. These findings were associated with reversible downregulation of metalloproteinase 9 and nephrin expression. Using transmission electron microscopy, we established that VEGF-A receptor-2 (VEGFR2) was expressed in podocytes and glomerular endothelial cells. We also found that VEGF164 induced VEGFR2 phosphorylation in podocytes. Further, we were able to co-immunoprecipitate VEGFR2 and nephrin using whole kidney lysates, confirming interaction in vivo. This implies that autocrine and paracrine VEGF-A signaling through VEGFR2 occurs in podocytes and may mediate the glomerular phenotype caused by VEGF164 overexpression. Thus, we suggest that podocyte VEGF164 overexpression in adult mice is sufficient to induce glomerular filtration barrier structural and functional abnormalities similar to those present in murine diabetic nephropathy.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Delma
authors.initials: D
authors.lastname: Veron
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Reidy
authors.forename: Claudia
authors.initials: C
authors.lastname: Bertuccio
authors.forename: Jason
authors.initials: J
authors.lastname: Teichman
authors.forename: Guillermo
authors.initials: G
authors.lastname: Villegas
authors.forename: Juan
authors.initials: J
authors.lastname: Jimenez
authors.forename: Wa
authors.initials: W
authors.lastname: Shen
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: David B
authors.initials: DB
authors.lastname: Thomas
authors.forename: Alda
authors.initials: A
authors.lastname: Tufro
mesh_terms: D000367:Age Factors; D000818:Animals; D019898:Autocrine Communication; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D050533:Glomerular Basement Membrane / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019899:Paracrine Communication; D010641:Phenotype; D010766:Phosphorylation; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C113267:nephrin; D040301:Vascular Endothelial Growth Factor Receptor-2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse