Pax2 Mutant Mice Have Dysregulated Nuclear Maintenance, Cell Proliferation, and Motility Associated with Abnormal Glomerular Repair
Bibliographic record
Abstract
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.
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 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".