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Abstract: TH-PO555

Mice with a Pax2 Missense Variant Are Susceptible to Experimental FSGS and Display Impaired Glomerular Repair

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Cunanan, Joanna, Toronto General Research Institute, Toronto, Ontario, Canada
  • Sharif, Bedra U., Toronto General Research Institute, Toronto, Ontario, Canada
  • Rajyam, Sriya, Toronto General Research Institute, Toronto, Ontario, Canada
  • Udwan, Khalil, Toronto General Research Institute, Toronto, Ontario, Canada
  • Rana, Akanchaya, Toronto General Research Institute, Toronto, Ontario, Canada
  • De Gregorio, Vanessa Sara, Toronto General Research Institute, Toronto, Ontario, Canada
  • Ricardo, Samantha, Toronto General Research Institute, Toronto, Ontario, Canada
  • Caparali, Emine Bilge, Toronto General Research Institute, Toronto, Ontario, Canada
  • John, Rohan, Toronto General Hospital, Toronto, Ontario, Canada
  • Farkona, Sofia, Toronto General Research Institute, Toronto, Ontario, Canada
  • Konvalinka, Ana, Toronto General Research Institute, Toronto, Ontario, Canada
  • Weins, Astrid, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Barua, Moumita, Toronto General Research Institute, Toronto, Ontario, Canada
Background

FSGS is a form of chronic kidney disease characterized by podocyte loss. Our team previously reported that PAX2 pathogenic missense variants account for 4% of adults with FSGS. PAX2 regulates glomerular development and its expression persists in adult parietal epithelial cells (PECs), postulated to serve as a reservoir for cells including podocytes. We hypothesize that in humans and mice with pathogenic PAX2 missense variants, PEC-mediated podocyte regeneration is impaired.

Methods

FSGS induced by Adriamycin was performed on wildtype mice and mice with a Pax2 missense variant (termed Pax2MV). Kidney tissue were analyzed by histology and immunostaining. Glomeruli were isolated and subjected to mass spectrometry (MS), analyzed by Gene Ontology (GO) Enrichment Analysis. Kidney tissue from relatives with PAX2-associated FSGS was also analyzed.

Results

At embryonic day 16.5, mouse wildtype kidneys showed overlapping expression of PAX2 and WT-1 in the condensed mesenchymal cells until PEC and podocyte differentiation, supporting a close lineage relationship. Pax2MV had reduced nephron number but displayed only minor differences in glomerular function at baseline. Adriamycin-injured Pax2MVmice showed more severe FSGS compared to wildtype, including decreased podocyte numbers and increased albuminuria. Adriamycin-injured Pax2MVmice showed PAX2-expressing glomerular tuft cells, which were rarely observed in injured wildtype and were similar to histological findings from PAX2-associated FSGS patients, suggesting a role of these ectopic PAX2-expressing cells in pathogenesis. GO processes obtained from isolated glomeruli demonstrated maladaptive repair in Pax2MV, including increased epithelial cell migration, decreased cell adhesion, de-regulated actin cytoskeleton dynamics, and in-utero embryonic development; while GO terms of normal repair mechanisms including regulation of cell morphogenesis, cell adhesion, cell-cell junction assembly, and actin cytoskeleton organization were enriched in wildtype.

Conclusion

Our findings support decreased glomerular regeneration in Pax2MV mice compared to wildtype. We are next pursuing glomerular single-cell RNA sequencing to characterize the role of PECs in this process.

Funding

  • Government Support – Non-U.S.