VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy

Karen L. Onions, Monica Gamez, Nicola R. Buckner, Siân L. 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 O. Bates, Andrew H.J. Salmon, Gavin I. Welsh, Simon C. Satchell, Rebecca R. Foster*

*Corresponding author for this work

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

11 Citations (Scopus)
238 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)172-187
Number of pages16
JournalDiabetes
Volume68
Issue number1
Early online date2 Nov 2018
DOIs
Publication statusPublished - Jan 2019

Fingerprint Dive into the research topics of 'VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy'. Together they form a unique fingerprint.

Cite this