title: Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy.
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.
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Oltean
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Ferguson
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Megan
authors.initials: M
authors.lastname: Stevens
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Chris
authors.initials: C
authors.lastname: Neal
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Amy
authors.initials: A
authors.lastname: Russell
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Amit
authors.initials: A
authors.lastname: Kaura
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Kenton P
authors.initials: KP
authors.lastname: Arkill
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Kirstie
authors.initials: K
authors.lastname: Harris
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Clare
authors.initials: C
authors.lastname: Symonds
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Katja
authors.initials: K
authors.lastname: Lacey
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Lihini
authors.initials: L
authors.lastname: Wijeyaratne
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gammons
authors.affiliation: School of Physiology and Pharmacology and Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom;
authors.forename: Emma
authors.initials: E
authors.lastname: Wylie
authors.affiliation: School of Life Sciences and.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hulse
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Chloe
authors.initials: C
authors.lastname: Alsop
authors.affiliation: Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom;
authors.forename: George
authors.initials: G
authors.lastname: Cope
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Damodaran
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Kai B
authors.initials: KB
authors.lastname: Betteridge
authors.affiliation: Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom;
authors.forename: Raina
authors.initials: R
authors.lastname: Ramnath
authors.affiliation: Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom;
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.affiliation: Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom;
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Foster
authors.affiliation: Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, Villigen, Switzerland;
authors.forename: Kurt
authors.initials: K
authors.lastname: Ballmer-Hofer
authors.affiliation: School of Physiology and Pharmacology and School of Life Sciences and.
authors.forename: Lucy F
authors.initials: LF
authors.lastname: Donaldson
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barratt
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Harper
authors.affiliation: Cancer Biology, Division of Oncology, School of Medicine, University of Nottingham, Nottingham, United Kingdom;
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.affiliation: School of Physiology and Pharmacology and Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom; Andy.Salmon@bristol.ac.uk David.Bates@nottingham.ac.uk.
authors.forename: Andrew H J
authors.initials: AH
authors.lastname: Salmon
mesh_terms: D000419:Albuminuria / Q000188:drug therapy; D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D019276:Glycocalyx / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: VEGF; VEGF-A; albuminuria; diabetes; diabetic nephropathy; endothelial glycocalyx; glomerulus; glycocalyx; permeability