Abstract: FR-PO389
Inducing Kidney Lymphangiogenesis in Development and Disease
Session Information
- Genetics, Development, Regeneration
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
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 David, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Deb, Dilip K., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Ni, Eric, Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania, United States
- Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background
Expansion of the lymphatic vasculature, or lymphangiogenesis, is observed in a number of kidney pathologies including AKI, diabetes, and transplant rejection. Additionally, lymphangiogenesis in these settings appears to be protective against injury and the progression of kidney fibrosis. As lymphangiogenesis is primarily driven by the secreted ligand vascular endothelial growth factor C (VEGF-C) through the receptor VEGFR-3, this signaling pathway is a potential target for future kidney therapeutics.
Methods
We generated a new transgenic mouse model to investigate the role of VEGF-C induced lymphangiogenesis in kidney development and response to injury. VEGF-C was overexpressed in nephron progenitor cells and the renal tubular compartment using the Six2Cre (Six2Vegf-C) and Pax8-CreERT2 (Pax8Vegf-C) driver strains respectively. We characterized the consequences of VEGF-C overexpression during development (Six2Vegf-C and Pax8Vegf-C) as well as adult mice after 1 week of induction (Pax8Vegf-C). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for micro-CT 3D imaging and histology with kidney lymphatics distinguished by co-immunofluorescence for the markers PDPN and VEGFR-3.
Results
Developmental overexpression of VEGF-C was detrimental to pup growth with increased mortality. Gross evaluation revealed enlarged kidneys with increased kidney-to-mouse weight ratio. Kidney histology and micro-CT imaging demonstrated large cystic lesions within the kidney hilum with marked expansion of the lymphatic capillary network throughout the kidney cortex. Inducing VEGF-C expression for 1 week in 4-week-old Pax8Vegf-C mice also resulted in an expansion of cortical lymphatic vessels, however without disruption of gross kidney architecture or reduced mouse viability. Single-cell RNA-seq of this model is currently pending.
Conclusion
Developmental and post-natal lymphangiogenesis is promoted by overexpression of VEGF-C. While developmental overexpression resulted in a more severe phenotype suggestive of cystic renal lymphangioma with increased mortality, augmenting VEGF-C expression in adult mice increased the lymphatic capillary density in the kidney without overt phenotypic consequence. This model enables further investigation into the function of lymphatic vessels during kidney injury.
Funding
- Private Foundation Support