Kidney Week

Abstract: TH-PO403

Pax2 Mutant Mice Have Dysregulated Nuclear Maintenance, Cell Proliferation, and Motility Associated with Abnormal Glomerular Repair

Session Information

• Development, Organoids, Injury, and Regeneration
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Authors

• Cunanan, Joanna, Division of Nephrology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

Joanna Cunanan, MS

• Benepal, Jasmeet Kaur, Division of Nephrology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

Jasmeet Kaur Benepal

• De Gregorio, Vanessa Sara, Division of Nephrology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

Vanessa Sara De Gregorio, MS

• Ricardo, Samantha, Division of Nephrology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

Samantha Ricardo

• Caparali, Emine Bilge, Division of Nephrology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

Emine Bilge Caparali, MD

• Konvalinka, Ana, Division of Nephrology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

Ana Konvalinka, MD, PhD

• Barua, Moumita, Division of Nephrology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

Moumita Barua, MD

Background

Focal segmental glomerulosclerosis (FSGS) is characterized by podocyte loss. Parietal epithelial cells (PECs) that express PAX2, a regulator of cellular and morphological changes during glomerular development, can regenerate podocytes after injury. We previously found that pathogenic PAX2 missense variants account for 4% of adult FSGS, and mutant PAX2+ PECs display impaired podocyte regeneration resulting in worsened FSGS in mice with a Pax2 missense variant (Pax2-MV) (Figure 1A-B). In this study, we report the molecular mechanisms of impaired podocyte regeneration in Pax2-MV.

Methods

FSGS was induced by Adriamycin (ADR) in Pax2-MV and wildtype mice. Isolated glomeruli were subjected to mass spectrometry-based proteomics and analyzed by Gene Ontology (GO) and Reactome pathway enrichment analysis.

Results

Downregulated processes in ADR-injured Pax2-MV compared to wildtype glomeruli include decreased metabolic processes and actin cytoskeleton structure regulation (Figure 1C), consistent with worsened podocyte loss observed in these mice. Upregulated processes in ADR-injured Pax2-MV include those involved in nuclear abnormalities, cell proliferation and motility (Figure 1D). These are consistent with the increased glomerular tuft cell proliferation observed in ADR-injured Pax2-MV mice. This suggests a maladaptive attempt to regenerate podocytes due to the lack of regeneration from mutant PAX2+ PECs.

Conclusion

In ADR-injured Pax2-MV, downregulated metabolism and cytoskeleton structure are typical signatures of podocyte loss. However, our novel findings are the upregulated pathways that are consistent with dysregulated PAX2 signaling, including nuclear abnormalities, cell proliferation and motility.

Funding

• Government Support – Non-U.S.