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: Delma Veron, Pardeep K Aggarwal, Heino Velazquez, Michael Kashgarian, Gilbert Moeckel, Alda Tufro
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 25 Issue 8 Pg. 1814-24 (Aug 2014) ISSN: 1533-3450 [Electronic] United States
• PMID: 24578128 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 by the American Society of Nephrology.

Chemical References

• Collagen Type IV
• Laminin
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Nitric Oxide Synthase Type III

Topics

• Animals
• Cell Culture Techniques
• Collagen Type IV (metabolism)
• Diabetic Nephropathies (etiology, metabolism, pathology)
• Glomerular Basement Membrane (metabolism, pathology)
• Laminin (metabolism)
• Mice
• Mice, Knockout
• Nitric Oxide Synthase Type III (genetics, physiology)
• Podocytes (metabolism)
• Proteinuria (etiology, metabolism, pathology)
• Renal Insufficiency (etiology, metabolism, pathology)
• Vascular Endothelial Growth Factor A (physiology)