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Abstract: PO0614

Mechanisms of VEGFR3 Signaling in Glomerular Development

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Donnan, Michael David, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Onay, Tuncer, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Scott, Rizaldy P., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Deb, Dilip K., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Thomas, Jean-Leon, Yale University, New Haven, Connecticut, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Dysregulation of Vascular Endothelial Growth Factor Receptor 3 (VEGFR3), known primarily for its role in lymphangiogenesis, is causally linked to the development of kidney diseases, including renal fibrosis and cystogenesis. However, the mechanisms of VEGFR3 signaling in kidney development, how it influences kidney disease, and the vascular beds involved remains uncertain.

Methods

We performed a detailed expression profile of VEGFR3 in the developing mouse kidney from embryonic age (E)13.5 through 3 months. We generated a new transgenic mouse model to investigate the role of Vegfr3 in the kidney vasculature (Vegfr3Flx). Conditional and cell-specific excision of the floxed allele was performed using the Rosa-rtTA-TetOCre, Cdh5-Cre/ERT2, and Prox1-Cre/ERT2 driver strains to evaluate global, pan-endothelial, and lymphatic endothelial cell deletion of Vegfr3 respectively. Additionally, breeding of mice carrying podocyte-specific deletion and overexpression of the VEGFR3 ligand, VEGF-C, are underway to define ligand-dependent and independent function of VEGFR3 in the glomerulus. Mice underwent a detailed phenotypic evaluation and kidney sections were processed for histology.

Results

VEGFR3 undergoes dynamic expression through development in glomerular endothelial cells (GECs), beginning with high expression in the angiogenic sprouts which invade the capillary cleft of the developing nephron. Constitutive deletion of Vegfr3 during mid-embryonic development resulted in reduced viability, lymphatic vascular defects, a reduction in kidney size, and a reduction in average cross-sectional glomerular count on serial sectioning (mean difference -3.767 ± 1.238, p <0.005). Additionally, deletion of Vegfr3 at embryonic day 11.5 demonstrated marked disruption of glomerular development with cavernous capillary malformations. Immunofluorescence and electron microscopy revealed glomerular structures surrounded by simplified podocytes, abnormal attachment of endothelial cells with reduced fenestrations, and poor formation of the glomerular basement membrane. VEGF-C mutant mice will be characterized once available.

Conclusion

VEGFR3 is expressed in GECs and is integral to normal glomerular development. The mechanisms of VEGFR3 signaling in GEC crosstalk with podocytes will be essential to define prior to the development of therapeutics targeting this pathway.

Funding

  • NIDDK Support