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

Stevens, Megan; Neal, Christopher R.; Salmon, Andrew H.J.; Bates, David O.; Harper, Steve J.; Oltean, Sebastian

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.

Citation

Stevens, M., Neal, C. R., Salmon, A. H., Bates, D. O., Harper, S. J., & Oltean, S. (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, 595(19), 6281-6298. https://doi.org/10.1113/jp274481

• Journal Article Type: Article
• Acceptance Date: May 17, 2017
• Online Publication Date: Jul 3, 2017
• Publication Date: Oct 1, 2017
• Deposit Date: May 24, 2017
• Publicly Available Date: Jul 3, 2017
• Journal: The Journal of Physiology
• Print ISSN: 0022-3751
• Electronic ISSN: 1469-7793
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 595
• Issue: 19
• Pages: 6281-6298
• DOI: https://doi.org/10.1113/jp274481
• Keywords: Vascular endothelial growth factor, alternative splicing, reno-protection
• Public URL: https://nottingham-repository.worktribe.com/output/885355
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1113/JP274481/full
• Contract Date: May 24, 2017