Abstract: PO0888
Vegfr3 Is Expressed in Fenestrated Microvascular Beds of the Kidney and Is Required for Glomerular Development
Session Information
- Development, Stem Cells, and Regenerative Medicine
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 500 Development, Stem Cells, and Regenerative Medicine
Authors
- Donnan, Michael D., 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
- Thomas, Jean-Leon, Yale University School of Medicine, New Haven, Connecticut, United States
- Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background
Chronic Kidney Disease is associated with pathological changes to the kidney vasculature which contribute to disease progression. Despite the recognized importance of vascular dysfunction in kidney disease, the mechanisms by which these changes occur are poorly understood, limiting therapeutic design. Dysregulation of Vascular Endothelial Growth Factor Receptor 3 (VEGFR3), known for its role in lymphangiogenesis, is causally linked to the development of kidney diseases, including renal fibrosis and cystogenesis. How VEGFR3 signaling influences kidney disease progression and the specific vascular beds involved remains unclear.
Methods
We performed a detailed expression analysis of Vegfr3 in the kidney using a Vegfr3-YFP reporter mouse line. We generated a new transgenic mouse model to investigate the role of Vegfr3 in the kidney vasculature (Vegfr3flox). Conditional and cell-specific excision of the floxed allele was performed using the Rosa-rtTA-TetOCre, Cdh5-Cre/ERT2, and PDPN-GFPCre driver strains to evaluate global, pan-endothelial, and lymphatic endothelial cell deletion of Vegfr3 respectively. Mice underwent a detailed phenotypic evaluation and kidney sections were processed for histology.
Results
Vegfr3 undergoes dynamic expression through development in several fenestrated blood microvascular beds of the kidney including the peritubular capillaries, the ascending vasa recta, and the glomerular capillaries. Constitutive deletion of Vegfr3 results in early embryonic lethality while induced deletion at later embryonic stages results in lymphatic pathologies including chylous ascites, blood-filled lymphatic vessels, and reduced viability. Both global and endothelial-cell specific deletion of Vegfr3 at embryonic day 11.5 resulted in marked disruption of glomerular development with cavernous capillary malformations. Immunofluorescence and electron microscopy revealed endothelial cell lined structures surrounded by immature podocytes with disrupted basement membrane development.
Conclusion
VEGFR3, while typically associated with lymphatic vessels, is expressed in fenestrated microvascular beds of the kidney and is required for glomerular development. These findings have important implications for the development of therapeutics targeting this pathway for the treatment of kidney disease.
Funding
- NIDDK Support