VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

Onions, Karen L.; Gamez, Monica; Buckner, Nicola R.; Betteridge, Kai B.; Desideri, Sara; Dallyn, Benjamin P.; Ramnath, Raina D.; Neal, Chris R.; Farmer, Louise K.; Mathieson, Peter W.; Gnudi, Luigi; Alitalo, Kari; Bates, David O.; Salmon, Andrew H.J.; Welsh, Gavin I.; Satchell, Simon C.; Foster, Rebecca R.

doi:10.2337/db18-0045

VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

Authors

Karen L. Onions

Monica Gamez

Nicola R. Buckner

Baker

Kai B. Betteridge

Sara Desideri

Benjamin P. Dallyn

Raina D. Ramnath

Chris R. Neal

Louise K. Farmer

Peter W. Mathieson

Luigi Gnudi

Kari Alitalo

DAVID BATES David.Bates@nottingham.ac.uk
Professor of Oncology

Andrew H.J. Salmon

Gavin I. Welsh

Simon C. Satchell

Rebecca R. Foster

Abstract

Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy.

Citation

Onions, K. L., Gamez, M., Buckner, N. R., Baker, S. L., Betteridge, K. B., Desideri, S., …Foster, R. R. (2019). VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy. Diabetes, 68(1), 172-187. https://doi.org/10.2337/db18-0045

Journal Article Type	Article
Acceptance Date	Oct 18, 2018
Online Publication Date	Nov 2, 2018
Publication Date	2019-01
Deposit Date	May 20, 2019
Journal	Diabetes
Print ISSN	0012-1797
Electronic ISSN	1939-327X
Publisher	American Diabetes Association
Peer Reviewed	Peer Reviewed
Volume	68
Issue	1
Pages	172-187
DOI	https://doi.org/10.2337/db18-0045
Keywords	Internal Medicine; Endocrinology, Diabetes and Metabolism
Public URL	https://nottingham-repository.worktribe.com/output/1478547
Publisher URL	https://diabetes.diabetesjournals.org/content/68/1/172