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

• Published in: Diabetologia Vol. 54; no. 5; pp. 1227 - 1241
• Main Authors: Veron, D., Bertuccio, C. A., Marlier, A., Reidy, K., Garcia, A. M., Jimenez, J., Velazquez, H., Kashgarian, M., Moeckel, G. W., Tufro, A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2011; Springer; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Chromatography, High Pressure Liquid; Creatinine - blood; Creatinine - urine; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - etiology; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Disease Models, Animal; Drug dosages; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glomerulonephritis; Human Physiology; Immunohistochemistry; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pediatrics; Podocytes - metabolism; Polymerase Chain Reaction; Semaphorin-3A - genetics; Semaphorin-3A - metabolism; Tandem Mass Spectrometry; Transgenic animals; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; United States > US; MMP; Semaphorin3a; Transgenic mice; Podocytes; VEGF-A; Proteinuria; Type 1 diabetes mellitus; Endocrinopathy; Glomerulonephritis; Kidney disease; Glomerulosclerosis; Immunopathology; Animal model; Urinary system disease; Rodentia; s MMP; Transgenic animal; Gene overexpression; Autoimmune disease; Podocyte; Vertebrata; Mammalia; Vascular endothelium growth factor; Mouse; Type 1 diabetes
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-2034-z

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.