Kidney Week

Abstract: TH-OR095

Pax2 Regulates a Transitional Parietal Epithelial Cell/Podocyte Cell State During Glomerular Repair via Nell-2

Session Information

• Shaping Pediatric Kidney Disease: Developmental Insights, Stem Cell Systems, Novel Biomarkers, and More
  October 22, 2026 | Location: Room 603, Convention Center
  Abstract Time: 05:10 PM - 05:20 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 700 Development, Stem Cells, and Regenerative Medicine

Authors

• Cunanan, Joanna, University Health Network, Toronto, Ontario, Canada

Joanna Cunanan, MS

• Rugolo, Francesco, University Health Network, Toronto, Ontario, Canada

Francesco Rugolo, PhD

• Zhang, Daniel, University Health Network, Toronto, Ontario, Canada

Daniel Zhang

• De Gregorio, Vanessa Sara, University Health Network, Toronto, Ontario, Canada

Vanessa Sara De Gregorio, MS

• Ricardo, Samantha, University Health Network, Toronto, Ontario, Canada

Samantha Ricardo

• Caparali, Emine Bilge, University Health Network, Toronto, Ontario, Canada

Emine Bilge Caparali, MD

• Romagnani, Paola, Universita degli Studi di Firenze, Florence, Tuscany, Italy

Paola Romagnani, MD, PhD

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

Moumita Barua, MD

Background

Podocyte loss drives glomerular disease, but regeneration mechanisms remain unclear. Parietal epithelial cells (PECs) are proposed progenitors based on PAX2 expression. We previously showed Pax2^A220G/+ mice have impaired podocyte regeneration and worsened disease. This study investigates mechanisms underlying defective PEC-to-podocyte repair in Pax2^A220G/+ glomeruli.

Methods

We performed single-nucleus RNA sequencing on 84,011 PEC-enriched glomerular nuclei from wildtype and Pax2^A220G/+ mice with or without Adriamycin injury (total N=77).

Results

Unbiased clustering identified distinct podocyte and PEC populations, including a transitional PEC/podocyte (PEC/POD) state (Fig1A). Injured Pax2^A220G/+ glomeruli showed increased podocyte loss and depletion of PEC/POD cells versus wild type (Fig1B), consistent with prior findings (Cunanan et al., 2024 AJP Renal). Pseudotime analysis revealed a regenerative trajectory where PEC-A cells with high Pax2 expression transition through PEC/POD intermediates toward podocytes. This trajectory was disrupted in Pax2^A220G/+ mice after injury, with reduced PEC/POD signatures (Fig1C). We identified Nell2 as a unique marker of PEC/POD cells, also expressed in podocytes, suggesting a shared transitional state (Fig1D). NELL2 is a secreted glycoprotein involved in neuronal differentiation and survival and may regulate similar fate transitions in the glomerulus. Reduced Nell2 expression in Pax2^A220G/+ PEC/POD cells after injury (Fig1D) supports its role in impaired regeneration.

Conclusion

These data define a PAX2-dependent PEC regenerative program and identify NELL2 as a candidate mediator of podocyte repair. Future work will use spatial transcriptomics to map PEC and podocyte subsets and functional assays to test whether NELL2 loss impairs migration, differentiation, and wound healing, supporting its role in regeneration.

Funding

• Private Foundation Support