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- Title
VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy.
- Authors
Onions, Karen L.; Gamez, Monica; Buckner, Nicola R.; Baker, Siân L.; 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.; Onions, Karen; Ramnath, Raina
- 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.
- Subjects
VASCULAR endothelial growth factors; ALBUMINS; GENE expression; DIABETIC nephropathies; ENDOTHELIAL cells; MESSENGER RNA; ANIMAL experimentation; CELL culture; CELL receptors; COMPARATIVE studies; EPITHELIAL cells; FLUORESCENT antibody technique; TYPE 1 diabetes; RESEARCH methodology; MEDICAL cooperation; RESEARCH; WESTERN immunoblotting; EVALUATION research; PRECIPITIN tests; GENOTYPES
- Publication
Diabetes, 2019, Vol 68, Issue 1, p172
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db18-0045