VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney
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...
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| Format: | Article |
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Wiley
2017
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| Online Access: | https://eprints.nottingham.ac.uk/43073/ |
| _version_ | 1848796633451462656 |
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| author | Stevens, Megan Neal, Christopher R. Salmon, Andrew H.J. Bates, David O. Harper, Steve J. Oltean, Sebastian |
| author_facet | Stevens, Megan Neal, Christopher R. Salmon, Andrew H.J. Bates, David O. Harper, Steve J. Oltean, Sebastian |
| author_sort | Stevens, Megan |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:51:05Z |
| format | Article |
| id | nottingham-43073 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:51:05Z |
| publishDate | 2017 |
| publisher | Wiley |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-430732020-05-04T19:09:31Z https://eprints.nottingham.ac.uk/43073/ 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 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. Wiley 2017-10-01 Article PeerReviewed Stevens, Megan, Neal, Christopher R., Salmon, Andrew H.J., Bates, David O., 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, 595 (19). pp. 6281-6298. ISSN 1469-7793 Vascular endothelial growth factor alternative splicing reno-protection http://onlinelibrary.wiley.com/doi/10.1113/JP274481/full doi:10.1113/JP274481 doi:10.1113/JP274481 |
| spellingShingle | Vascular endothelial growth factor alternative splicing reno-protection Stevens, Megan Neal, Christopher R. Salmon, Andrew H.J. Bates, David O. Harper, Steve J. Oltean, Sebastian VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney |
| title | VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney |
| title_full | VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney |
| title_fullStr | VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney |
| title_full_unstemmed | VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney |
| title_short | VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney |
| title_sort | vegf-a165b protects against proteinuria in a mouse model with progressive depletion of all endogenous vegf-a splice isoforms from the kidney |
| topic | Vascular endothelial growth factor alternative splicing reno-protection |
| url | https://eprints.nottingham.ac.uk/43073/ https://eprints.nottingham.ac.uk/43073/ https://eprints.nottingham.ac.uk/43073/ |