Karen L. Onions
VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy
Authors
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 |
You might also like
Looking Under the Lamppost: The Search for New Cancer Targets in the Human Kinome
(2022)
Journal Article
Non?invasive measurement of retinal permeability in a diabetic rat model
(2020)
Journal Article
Phenotypic and functional translation of IL33 genetics in asthma
(2020)
Journal Article