VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney

Stevens, Megan and Neal, Christopher R. and Salmon, Andrew H.J. and Bates, David O. and Harper, Steve J. and Oltean, Sebastian (2017) VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney. Journal of Physiology . ISSN 1469-7793

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Abstract

Chronic kidney disease (CKD) is strongly associated with a decrease in the expression of VEGF-A. However, little is known about the contribution of VEGF-A splice isoforms to kidney physiology and pathology. Previous studies suggest that the splice isoform VEGF-A165b (resulting from alternative usage of a 3’ splice site in the terminal exon) is protective for kidney function. We show here, in a quad-transgenic model, that over-expression of VEGF-A165b alone is sufficient to rescue the increase in proteinuria as well as glomerular water permeability in the context of progressive depletion of all VEGF-A isoforms from the podocytes. Ultrastructural studies show that the glomerular basement membrane is thickened, podocyte slit width is increased and sub-podocyte space coverage is reduced when VEGF-A is depleted, all of which are rescued in VEGF-A165b over-expressors. VEGF-A165b restores the expression of PECAM-1 in glomerular endothelial cells and glomerular capillary circumference. Mechanistically, it increases VEGFR2 expression both in vivo and in vitro and down-regulates genes involved in migration and proliferation of endothelial cells, otherwise up-regulated by the canonical isoform VEGF-A165. Our study indicates that manipulation of VEGF-A splice isoforms could be a novel therapeutic avenue in chronic glomerular disease.

Item Type: Article
Keywords: Vascular endothelial growth factor, alternative splicing, reno-protection
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Cancer and Stem Cells
Identification Number: 10.1113/JP274481
Depositing User: Bates, David
Date Deposited: 24 May 2017 10:05
Last Modified: 13 Aug 2017 05:53
URI: http://eprints.nottingham.ac.uk/id/eprint/43073

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