Overexpression of VEGF165b in podocytes reduces glomerular permeability.
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.
Qiu
Yan
Y
Microvascular Research Laboratories, Department Physiology and Pharmacology, Bristol Heart Institute, Preclinical Veterinary School, Southwell Street, Bristol, BS2 8EJ, UK.
Ferguson
Joanne
J
Oltean
Sebastian
S
Neal
Chris R
CR
Kaura
Amit
A
Bevan
Heather
H
Wood
Emma
E
Sage
Leslie M
LM
Lanati
Silvia
S
Nowak
Dawid G
DG
Salmon
Andy H J
AH
Bates
David
D
Harper
Steve J
SJ
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*
D042461:Vascular Endothelial Growth Factor A