Vascular endothelial growth factor-A165b is protective and restores endothelial glycocalyx in diabetic nephropathy

Oltean, Sebastian; Qiu, Yan; Ferguson, Joanne K.; Stevens, Megan; Neal, Chris; Russell, Amy; Kaura, Amit; Arkill, Kenton P.; Harris, Kirstie; Symonds, Clare; Lacey, Katja; Wijeyaratne, Lihini; Gammons, Melissa; Wylie, Emma; Hulse, Richard P.; Alsop, Chloe; Cope, George; Damodaran, Gopinath; Betteridge, Kai B.; Ramnath, Raina; Satchell, Simon C.; Foster, Rebecca R.; Ballmer-Hofer, Kurt; Donaldson, Lucy F.; Barratt, Jonathan; Baelde, Hans J.; Harper, Steven J.; Bates, David O.; Salmon, Andrew H.J.

Abstract

Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

Citation

Oltean, S., Qiu, Y., Ferguson, J. K., Stevens, M., Neal, C., Russell, A., Kaura, A., Arkill, K. P., Harris, K., Symonds, C., Lacey, K., Wijeyaratne, L., Gammons, M., Wylie, E., Hulse, R. P., Alsop, C., Cope, G., Damodaran, G., Betteridge, K. B., Ramnath, R., …Salmon, A. H. (2015). Vascular endothelial growth factor-A165b is protective and restores endothelial glycocalyx in diabetic nephropathy. Journal of the American Society of Nephrology, 26(8), https://doi.org/10.1681/ASN.2014040350

• Journal Article Type: Article
• Acceptance Date: Oct 15, 2014
• Publication Date: Aug 1, 2015
• Deposit Date: Aug 28, 2018
• Print ISSN: 1046-6673
• Electronic ISSN: 1533-3450
• Publisher: American Society of Nephrology
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: 8
• DOI: https://doi.org/10.1681/ASN.2014040350
• Public URL: https://nottingham-repository.worktribe.com/output/1104781
• Publisher URL: https://jasn.asnjournals.org/content/26/8/1889
• PMID: 25542969
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