Parietal Epithelial Cell Transcriptional Profiling from Pax2 Mutant Mice Is Consistent with Impaired Regeneration After Podocyte Injury
Bibliographic record
Abstract
Background: Podocyte loss in glomerular disease is difficult to treat due to their terminal differentiation. Parietal epithelial cells (PECs), which express developmental markers like PAX2, may contribute to podocyte regeneration. Our previous work suggests impaired PEC-mediated repair in mice with a Pax2 missense mutation, which develop worsened FSGS after podocyte injury compared to controls. Here, we used single nucleus RNA sequencing (snRNA-seq) to investigate the molecular basis of this defect, focusing on PEC cell clusters post-injury. Methods: Glomeruli from Adriamycin-injured Pax2 mutant mice were isolated using Dynabeads, minimizing collagenous digestion to preserve the Bowman’s capsule for PEC enrichment, which are often missed in single cell RNA sequencing studies due to their sparsity. snRNA-seq (10X Genomics) was processed with Seurat in RStudio. Cell types were identified using canonical markers (Chung et al., JASN 2020), and Gene Ontology (GO) analysis was performed. Results: In PECs, GO analysis revealed downregulation of pathways essential for podocyte regeneration, including podocyte and glomerular epithelial development, adherens junction assembly, IL-6 signaling, Hippo signaling, and plasma membrane organization. These changes suggest impaired epithelial integrity, differentiation, and reparative signaling. In contrast, PECs showed upregulation of metabolic pathways (e.g., proline, glucuronate metabolism), possibly reflecting a maladaptive stress response. The POD/PEC cluster showed downregulated developmental, adhesion, and morphogenesis pathways, indicating impaired differentiation. Although anti-apoptotic signaling was upregulated in POD/PEC cells, this occurred without regenerative program activation. Conclusion: Together, these findings suggest that after Adriamycin-induced podocyte injury, PECs and transitional POD/PEC cells in Pax2 mutant glomeruli fail to activate key developmental programs needed for podocyte regeneration and instead adopt transcriptional states that are metabolically altered but likely not pro-reparative.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".