Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

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

Research output: Contribution to journalArticle (Academic Journal)peer-review

81 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1889-1904
JournalJournal of the American Society of Nephrology
Volume26
Issue number8
DOIs
Publication statusPublished - Aug 2015

Bibliographical note

Copyright © 2014 by the American Society of Nephrology.

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