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01.05.2011 | Article

Podocyte vascular endothelial growth factor (Vegf ₁₆₄) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes

verfasst von: D. Veron, C. A. Bertuccio, A. Marlier, K. Reidy, A. M. Garcia, J. Jimenez, H. Velazquez, M. Kashgarian, G. W. Moeckel, A. Tufro

Erschienen in: Diabetologia | Ausgabe 5/2011

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Abstract

Aims/hypothesis

The pathogenic role of excessive vascular endothelial growth factor (VEGF)-A in diabetic nephropathy has not been defined. We sought to test whether increased podocyte VEGF-A signalling determines the severity of diabetic glomerulopathy.

Methods

Podocyte-specific, doxycycline-inducible Vegf ₁₆₄ (the most abundant Vegfa isoform) overexpressing adult transgenic mice were made diabetic with low doses of streptozotocin and examined 12 weeks after onset of diabetes. We studied diabetic and non-diabetic transgenic mice fed a standard or doxycycline-containing diet. VEGF-A and albuminuria were measured by ELISA, creatinine was measured by HPLC, renal morphology was examined by light and electron microscopy, and gene expression was assessed by quantitative PCR, immunoblotting and immunohistochemistry.

Results

Podocyte Vegf ₁₆₄ overexpression in our mouse model of diabetes resulted in advanced diabetic glomerulopathy, characterised by Kimmelstiel–Wilson-like nodular glomerulosclerosis, microaneurysms, mesangiolysis, glomerular basement membrane thickening, podocyte effacement and massive proteinuria associated with hyperfiltration. It also led to increased VEGF receptor 2 and semaphorin3a levels, as well as nephrin and matrix metalloproteinase-2 downregulation, whereas circulating VEGF-A levels were similar to those in control diabetic mice.

Conclusions/interpretation

Collectively, these data demonstrate that increased podocyte Vegf ₁₆₄ signalling dramatically worsens diabetic nephropathy in a streptozotocin-induced mouse model of diabetes, resulting in nodular glomerulosclerosis and massive proteinuria. This suggests that local rather than systemic VEGF-A levels determine the severity of diabetic nephropathy and that semaphorin3a signalling and matrix metalloproteinase-2 dysregulation are mechanistically involved in severe diabetic glomerulopathy.

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Titel: Podocyte vascular endothelial growth factor (Vegf 164 ) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes
verfasst von: D. Veron
C. A. Bertuccio
A. Marlier
K. Reidy
A. M. Garcia
J. Jimenez
H. Velazquez
M. Kashgarian
G. W. Moeckel
A. Tufro
Publikationsdatum: 01.05.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 5/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-010-2034-z

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Podocyte vascular endothelial growth factor (Vegf ₁₆₄) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes

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Methods

Results

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