ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO389

Inducing Kidney Lymphangiogenesis in Development and Disease

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
  • 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