ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

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-PO927

A Role for the Developmental Gene Pax2 in the Adult Kidney After Glomerular Injury

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Sharif, Bedra U., University Health Network, Toronto, Ontario, Canada
  • Udwan, Khalil, University Health Network, Toronto, Ontario, Canada
  • John, Rohan, University Health Network, Toronto, Ontario, Canada
  • Barua, Moumita, University Health Network, Toronto, Ontario, Canada
Background

Pax2 is a member of the Pax family of highly conserved transcription factors that play important roles during development. Pax2 is essential for mammalian kidney organogenesis, without which the kidneys fail to form. We have previously reported that heterozygous missense mutations in Pax2 lead to focal and segmental glomerulosclerosis (FSGS) in ~5% of adults with the disorder. FSGS is a clinico-pathologic entity characterized by proteinuria and podocyte foot process effacement. We have obtained a mouse model with a Pax2 missense mutation to further investigate the mechanism by which the glomerular defect occurs.

Methods

We employed immunohistochemistry, electron microscopy, and Western blotting to examine kidneys from wild type and Pax2 mutant mice that were subjected to Adriamycin (ADR) administered through tail vein injections.

Results

Mice homozygous for Pax2 A220G (Pax2A220G/A220G) develop dysplastic kidneys and are not viable though they survive to late gestation (E18.5). As expected, heterozygous Pax2A220G/+ mice display smaller kidneys and reduced nephron number with no other obvious glomerular defects. Surprisingly, we find that Pax2 expression still persists widely in the adult kidney, both in the glomerular and tubular compartments. Challenging Pax2A220G/+ mice with Adriamycin (ADR) recapitulated human FSGS with mutant mice more susceptible to injury compared to wildtype. Ki-67 staining revealed increased glomerular cell proliferation, that was not due to infiltrating immune cells, and caspase-3 staining demonstrated increased parietal epithelial cell (PEC) apoptosis that was observed in mutant but not wildtype mice.

Conclusion

We have demonstrated that a Pax2 heterozygous missense mutation renders the adult mouse kidney more susceptible to podocyte injury, approximating FSGS observed in humans. We postulate a role for Pax2 in the repair of injured glomeruli that may involve parietal epithelial cells.

Funding

  • Private Foundation Support