Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes

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

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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 Vegf164 (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 Vegf164 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 Vegf164 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.

Original languageEnglish (US)
Pages (from-to)1227-1241
Number of pages15
JournalDiabetologia
Volume54
Issue number5
DOIs
StatePublished - May 2011

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Podocytes
Diabetic Nephropathies
Type 1 Diabetes Mellitus
Vascular Endothelial Growth Factor A
Doxycycline
Matrix Metalloproteinase 2
Streptozocin
Proteinuria
Transgenic Mice
Vascular Endothelial Growth Factor Receptor-2
Glomerular Basement Membrane
Albuminuria
Immunoblotting
Creatinine
Electron Microscopy
Protein Isoforms
Down-Regulation
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
High Pressure Liquid Chromatography

Keywords

  • MMP
  • Podocytes
  • Proteinuria
  • Semaphorin3a
  • Transgenic mice
  • Type 1 diabetes mellitus
  • VEGF-A

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. / Veron, D.; Bertuccio, C. A.; Marlier, A.; Reidy, Kimberly J.; Garcia, A. M.; Jimenez, J.; Velazquez, H.; Kashgarian, M.; Moeckel, G. W.; Tufro, A.

In: Diabetologia, Vol. 54, No. 5, 05.2011, p. 1227-1241.

Research output: Contribution to journalArticle

Veron, D, Bertuccio, CA, Marlier, A, Reidy, KJ, Garcia, AM, Jimenez, J, Velazquez, H, Kashgarian, M, Moeckel, GW & Tufro, A 2011, 'Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes', Diabetologia, vol. 54, no. 5, pp. 1227-1241. https://doi.org/10.1007/s00125-010-2034-z
Veron, D. ; Bertuccio, C. A. ; Marlier, A. ; Reidy, Kimberly J. ; Garcia, A. M. ; Jimenez, J. ; Velazquez, H. ; Kashgarian, M. ; Moeckel, G. W. ; Tufro, A. / Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. In: Diabetologia. 2011 ; Vol. 54, No. 5. pp. 1227-1241.
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AU - Marlier, A.

AU - Reidy, Kimberly J.

AU - Garcia, A. M.

AU - Jimenez, J.

AU - Velazquez, H.

AU - Kashgarian, M.

AU - Moeckel, G. W.

AU - Tufro, A.

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