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Kidney Week

Abstract: FR-OR041

Disruptions to Neurovascular Patterning Affect Kidney Development and Adult Function

Session Information

  • Development and Stem Cells
    November 08, 2019 | Location: 152, Walter E. Washington Convention Center
    Abstract Time: 04:30 PM - 04:42 PM

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Honeycutt, Samuel E., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Hardesty, Deanna Marie, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • O'Brien, Lori L., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
Background

Kidney neurovascular networks are critical to maintaining mammalian physiology and homeostasis. Despite their important roles, we know little about how they form and pattern in the embryonic kidney or how neurovascular interactions affect kidney development. Netrin-1 (Ntn1) is a secreted ligand critical for neurovascular guidance during embryogenesis and is highly expressed by stromal progenitors. Therefore, netrin-1 is an ideal candidate for regulating these processes during kidney development. In turn, the neurovascular networks can release factors important for development and maturation of tissues. We set out to identify candidate angiocrine factors released by the kidney endothelium and confirm their role in renal development.

Methods

We conditionally deleted Ntn1 from kidney stromal progenitors. We utilized immunofluorescent staining, lightsheet and confocal microscopy, and cellular analyses to interrogate the embryonic phenotype. Adult kidneys were assessed for EPO and Renin production, subjected to histological analyses, and blood collected from animals for clinical chemistry. Additionally, we developed a novel vascular labeling and imaging methodology to generate 3D images for our adult analyses. We utilized publicly available single-cell RNA-seq and array data to identify putative angiocrine factors produced by the developing kidney vasculature.

Results

Conditional deletion of Ntn1 results in hypoplastic kidneys and aberrant patterning of the neurovascular networks. Nephron progenitor proliferation is reduced and nephrogenesis is extended. Vasculature mis-patterning persists in the adult Ntn1 mutant kidney. These animals have altered EPO and red blood cell production, and abnormal histology. Utilizing expression data, we identified Insulin-like growth factor 1 (Igf1) as a putative angiocrine factor in the developing kidney. Current efforts focus on conditional Igf1 deletion from the kidney vasculature and assessing the effects on development.

Conclusion

Taken together, our studies provide novel insights into the establishment of neurovascular networks in the developing kidney and implications for adult function. Such findings will help inform regenerative strategies and efforts to engineer kidneys de novo, where establishing proper kidney filtration and nephron function will be essential.

Funding

  • Private Foundation Support