Loss of genome maintenance accelerates podocyte damage and aging
Bibliographic record
Abstract
Abstract DNA repair is essential for preserving genome integrity and ensuring cellular functionality and survival. Podocytes, post-mitotic glomerular epithelial cells, bear limited regenerative capacity, and their survival is indispensable to maintain the function of the kidney’s filtration units. While podocyte depletion is a hallmark of the aging process and of many proteinuric kidney diseases, the underlying factors remain unclear. We investigated DNA repair in podocyte diseases by using a constitutive and an inducible podocyte-specific knockout mouse model for Ercc1, a multifunctional endonuclease cofactor involved in nucleotide excision repair (NER), interstrand crosslink (ICL) repair, and DNA double-strand break (DSB) repair. We assessed the consequences of Ercc1 loss in vivo, complemented by mechanistical in vitro studies of induced DNA damage in cultured podocytes. Furthermore, we characterized DNA damage-related alterations in mouse and human renal tissue of different ages as well as in patient biopsies with minimal change disease and focal segmental glomerulosclerosis. Podocyte-specific Ercc1 knockout resulted in accumulation of DNA damage with ensuing proteinuria, podocyte loss, glomerulosclerosis, renal insufficiency, and reduced lifespan. The response to genomic stress was different to the pattern reported in other cell types, as podocytes activated mTORC1 signaling upon DNA damage in vitro and in vivo . The induced mTORC1 activation was abrogated by inhibiting DNA damage response through DNA-PK and ATM kinases in vitro . Moreover, pharmacological inhibition of mTORC1 modulated the development of glomerulosclerosis in Ercc1 -deficient mice. Perturbed DNA repair gene expression and genomic stress was also detected in podocytes of human focal segmental glomerulosclerosis, characterized by podocyte loss. Beyond that, DNA damage accumulation occurred in podocytes of healthy aging mice and humans. These findings reveal that genome maintenance is crucial for podocyte maintenance, linked to the mTORC1 pathway, and involved in the aging process as well as in the development of glomerulosclerosis, potentially serving as a therapeutic target in the future.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".