Kidney Week

Abstract: FR-PO927

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

Session Information

• Glomerular Diseases: Podocyte Biology - II
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Sharif, Bedra U., University Health Network, Toronto, Ontario, Canada

Bedra U. Sharif,

• Udwan, Khalil, University Health Network, Toronto, Ontario, Canada

Khalil Udwan,

• John, Rohan, University Health Network, Toronto, Ontario, Canada

Rohan John,

• Barua, Moumita, University Health Network, Toronto, Ontario, Canada

Moumita Barua,

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 (Pax2^A220G/A220G) develop dysplastic kidneys and are not viable though they survive to late gestation (E18.5). As expected, heterozygous Pax2^A220G/+ 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 Pax2^A220G/+ 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