Heterozygous Col4a3 Mutation Increases Susceptibility to Doxorubicin-Induced Podocytopathy
Bibliographic record
Abstract
Background: Podocyte injury and loss are key initiating events in Focal segmental glomerulosclerosis (FSGS) development. While COL4A3 and COL4A4 variants were once linked to benign thin basement membrane nephropathy, they are now recognized as the most frequent genetic causes of adult-onset FSGS. The mechanisms linking COL4-related glomerular basement membrane (GBM) defects to podocyte injury remain poorly understood. Methods: To assess the impact of Col4a3 mutations on susceptibility to podocyte injury, we induced podocytopathy by administering intravenous doxorubicin (Dox; 8 mg/kg) to wild-type (WT; Col4a3+/+) and heterozygous (HET; Col4a3+/-) male mice on a 129S1/SvImJ background. Their littermates that received saline served as controls. Dox or saline were administered at 6 weeks of age, and mice were euthanized at 10 weeks of age. Urine and blood samples were collected for biochemical analysis, and kidney tissues were examined histologically. Results: HET mice with saline injection showed no significant differences in the urinary albumin-creatinine ratio (UACR), blood urea nitrogen, or histological features compared to WT mice with saline injection. HET mice with Dox exhibited a significantly higher UACR than WT mice with Dox, while there was no difference in body weight, kidney weight, or BUN between the two groups. In addition, HET mice with Dox had increased glomerulosclerosis score (PAS staining) and greater tubulointerstitial fibrosis (Sirius red staining) compared to WT mice with Dox. Conclusion: Heterozygous Col4a3 mutations increase susceptibility to Dox-induced podocytopathy. These findings support a pathogenic role for GBM abnormalities in the development of FSGS. Ongoing studies aim to elucidate the underlying molecular mechanisms.
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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 | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
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".