The alternatively spliced anti-angiogenic family of VEGF isoforms VEGFxxxb in human kidney development.
OBJECTIVE
Vascular endothelial growth factor (VEGF), required for renal development, is generated by alternative splicing of 8 exons to produce two families, pro-angiogenic VEGF(xxx), formed by proximal splicing in exon 8 (exon 8a), and anti-angiogenic VEGF(xxx)b, generated by distal splicing in exon 8 (exon 8b). VEGF(165)b, the first described exon 8b-containing isoform, antagonises VEGF(165) and is anti-angiogenic in vivo.


METHODS
Using VEGF(xxx)b-specific antibodies, we investigated its expression quantitatively and qualitatively in developing kidney, and measured the effect of VEGF(165)b on renal endothelial and epithelial cells.


RESULTS
VEGF(xxx)b formed 45% of total VEGF protein in adult renal cortex, and VEGF(165)b does not increase glomerular endothelial cell permeability, it inhibits migration, and is cytoprotective for podocytes. During renal development, VEGF(xxx)b was expressed in the condensed vesicles of the metanephros, epithelial cells of the comma-shaped bodies, invading endothelial cells and epithelial cells of the S-shaped body, and in the immature podocytes. Expression reduced as the glomerulus matured.


CONCLUSIONS
These results show that the anti-angiogenic VEGF(xxx)b isoforms are highly expressed in adult and developing renal cortex, and suggest that the VEGF(xxx)b family plays a role in glomerular maturation and podocyte protection by regulating the pro-angiogenic pro-permeability properties of VEGF(xxx) isoforms.
Bevan
Heather S
HS
Microvascular Research Laboratories, Department of Physiology, University of Bristol, Bristol, UK.
van den Akker
Nynke M S
NM
Qiu
Yan
Y
Polman
Japke A E
JA
Foster
Rebecca R
RR
Yem
Justin
J
Nishikawa
Ali
A
Satchell
Simon C
SC
Harper
Steven J
SJ
Gittenberger-de Groot
Adriana C
AC
Bates
David O
DO
D000375:Aging / Q000378:metabolism*; D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics* / Q000378:metabolism*
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D020033:Protein Isoforms; D022821:RNA Splice Sites; C467485:VEGFB protein, human; D042561:Vascular Endothelial Growth Factor B