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Kidney Week

Abstract: FR-PO761

Defining the Role of Vascular Endothelial Growth Factor 3 (VEGFR3) in the Fenestrated Microvasculature Beds of the Kidney

Session Information

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
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

The vasculature of the mammalian kidney is heterogeneous due to the need to carry out highly specialized functions such as glomerular filtration, urinary concentration and electrolyte homeostasis. The vascular endothelial growth factor tyrosine kinase receptor 3 (VEGFR3) is best known for its essential role in lymphatic endothelial cell proliferation however it is also highly expressed in fenestrated microvascular beds in several tissues including the kidney. In contrast to VEGFR2, functions of VEGFR3 in kidney vasculature are poorly understood but have been implicated in a number of kidney pathologies including cystogenesis and renal fibrosis. We hypothesize that VEGFR3 is required for proper maturation of renal microvascular beds and that loss of VEGFR3 will accelerate progression of kidney disease.

Methods

We generated a new conditional transgenic mouse model to study Vegfr3 function in the kidney vasculature (Vegfr3flox). This model allows for endothelial-specific excision of the floxed Vegfr3 allele using the vascular-specific Cre driver strain Cdh5-Cre/ERT2. We evaluated a Vegfr3-YFP reporter mouse to analyze expression of Vegfr3 within the microvascular beds of the kidney. Mouse kidney sections were processed for histology and immunofluorescence.

Results

Analysis of Vegfr3-YFP reporter mice demonstrates that Vegfr3 is expressed in multiple fenestrated microvascular beds of the kidney including the glomerulus, ascending vasa recta, and peritubular capillaries. Twenty percent of mice heterozygous for the intact neo-cassette-containing floxed Vegfr3 allele (Vegfr3+/neo ) exhibit chylous ascites suggesting disruption of the neo-cassette containing VEGFR3 allele. These mice demonstrate reduced viability and exhibit several vascular pathologies including blood filled lymphatic capillaries and hemorrhage of intestinal Peyer’s patches.

Conclusion

VEGFR3 is expressed in many specialized microvascular beds within the kidney and may play an important role in their development and maintenance. We have generated a novel conditional mouse model to comprehensively study the role of VEGFR3 in renal vasculature. Using this model to perform time dependent endothelial-specific knockout of Vegfr3 through development will provide valuable insights into specialized functions of fenestrated microvascular beds in the kidney.

Funding

  • NIDDK Support