title: Overexpression of VEGF165b in podocytes reduces glomerular permeability.
abstract: The observation that therapeutic agents targeting vascular endothelial growth factor-A (VEGF-A) associate with renal toxicity suggests that VEGF plays a role in the maintenance of the glomerular filtration barrier. Alternative mRNA splicing produces the VEGF(xxx)b family, which consists of antiangiogenic peptides that reduce permeability and inhibit tumor growth; the contribution of these peptides to normal glomerular function is unknown. Here, we established and characterized heterozygous and homozygous transgenic mice that overexpress VEGF(165)b specifically in podocytes. We confirmed excess production of glomerular VEGF(165)b by reverse transcriptase-PCR, immunohistochemistry, and ELISA in both heterozygous and homozygous animals. Macroscopically, the mice seemed normal up to 18 months of age, unlike the phenotype of transgenic podocyte-specific VEGF(164)-overexpressing mice. Animals overexpressing VEGF(165)b, however, had a significantly reduced normalized glomerular ultrafiltration fraction with accompanying changes in ultrastructure of the glomerular filtration barrier on the vascular side of the glomerular basement membrane. These data highlight the contrasting properties of VEGF splice variants and their impact on glomerular function and phenotype.
authors.affiliation: Microvascular Research Laboratories, Department Physiology and Pharmacology, Bristol Heart Institute, Preclinical Veterinary School, Southwell Street, Bristol, BS2 8EJ, UK.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
authors.forename: Joanne
authors.initials: J
authors.lastname: Ferguson
authors.forename: Sebastian
authors.initials: S
authors.lastname: Oltean
authors.forename: Chris R
authors.initials: CR
authors.lastname: Neal
authors.forename: Amit
authors.initials: A
authors.lastname: Kaura
authors.forename: Heather
authors.initials: H
authors.lastname: Bevan
authors.forename: Emma
authors.initials: E
authors.lastname: Wood
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Sage
authors.forename: Silvia
authors.initials: S
authors.lastname: Lanati
authors.forename: Dawid G
authors.initials: DG
authors.lastname: Nowak
authors.forename: Andy H J
authors.initials: AH
authors.lastname: Salmon
authors.forename: David
authors.initials: D
authors.lastname: Bates
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Harper
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D007678:Kidney Glomerulus / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010539:Permeability; D050199:Podocytes / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A