title: Podocyte-specific VEGF-a gain of function induces nodular glomerulosclerosis in eNOS null mice.
abstract: VEGF-A and nitric oxide are essential for glomerular filtration barrier homeostasis and are dysregulated in diabetic nephropathy. Here, we examined the effect of excess podocyte VEGF-A on the renal phenotype of endothelial nitric oxide synthase (eNOS) knockout mice. Podocyte-specific VEGF(164) gain of function in eNOS(-/-) mice resulted in nodular glomerulosclerosis, mesangiolysis, microaneurysms, and arteriolar hyalinosis associated with massive proteinuria and renal failure in the absence of diabetic milieu or hypertension. In contrast, podocyte-specific VEGF(164) gain of function in wild-type mice resulted in less pronounced albuminuria and increased creatinine clearance. Transmission electron microscopy revealed glomerular basement membrane thickening and podocyte effacement in eNOS(-/-) mice with podocyte-specific VEGF(164) gain of function. Furthermore, glomerular nodules overexpressed collagen IV and laminin extensively. Biotin-switch and proximity ligation assays demonstrated that podocyte-specific VEGF(164) gain of function decreased glomerular S-nitrosylation of laminin in eNOS(-/-) mice. In addition, treatment with VEGF-A decreased S-nitrosylated laminin in cultured podocytes. Collectively, these data indicate that excess glomerular VEGF-A and eNOS deficiency is necessary and sufficient to induce Kimmelstiel-Wilson-like nodular glomerulosclerosis in mice through a process that involves deposition of laminin and collagen IV and de-nitrosylation of laminin.
authors.affiliation: Department of Pediatrics.
authors.forename: Delma
authors.initials: D
authors.lastname: Veron
authors.affiliation: Department of Pediatrics.
authors.forename: Pardeep K
authors.initials: PK
authors.lastname: Aggarwal
authors.affiliation: Department of Internal Medicine, and.
authors.forename: Heino
authors.initials: H
authors.lastname: Velazquez
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moeckel
authors.affiliation: Department of Pediatrics, alda.tufro@yale.edu.
authors.forename: Alda
authors.initials: A
authors.lastname: Tufro
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D024141:Collagen Type IV / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000502:physiology*; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051437:Renal Insufficiency / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D024141:Collagen Type IV; D007797:Laminin; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D052250:Nitric Oxide Synthase Type III