Initial Autophagic Protection Switches to Disruption of Autophagic Flux by Lysosomal Instability during Cadmium Stress Accrual in Renal NRK‐52E Cells
Bibliographic record
Abstract
The renal proximal tubule (PT) is the major target of cadmium (Cd 2+ ) toxicity where Cd 2+ causes stress and apoptosis. Autophagy is induced by cell stress, e.g. endoplasmic reticulum (ER) stress, and may contribute to cell survival or death. The role of autophagy in Cd 2+ ‐induced nephrotoxicity remains unsettled due to contradictory results and lack of evidence for autophagic machinery damage by Cd 2+ . Cd 2+ ‐induced autophagy in the rat kidney PT cell line NRK‐52E and its role in cell death was investigated. Autophagy markers LC3‐II and p62 indicate rapid induction of autophagic flux by Cd 2+ (5–10μM) after 1h, accompanied by ER stress (increased p‐PERK, p‐eIF2α, CHOP). Cd 2+ exposure exceeding 3h results in p62/LC3‐II accumulation, but diminished effect of lysosomal inhibitors (bafilomycin A1, pepstatin A+E64d) on p62/LC3‐II levels, indicating decreased autophagic flux and cargo degradation. At 24h exposure, Cd 2+ (5–25μM) activates intrinsic apoptotic pathways (Bax/Bcl‐2, PARP1), which are not evident earlier (≤ 6h) despite decreased cell viability by MTT assay. Autophagy inducer rapamycin (100nM) does not overcome autophagy inhibition or Cd 2+ ‐induced cell viability loss. The autophagosome‐lysosome fusion inhibitor liensinine (5μM) increases CHOP and Bax/Bcl‐2 dependent apoptosis by low Cd 2+ stress, but not by high Cd 2+ . Lysosomal instability by Cd 2+ (5μM; 6h) is indicated by increased cellular sphingomyelin and membrane fluidity and decreased cathepsins and LAMP1. The data suggest dual and temporal impact of Cd 2+ on autophagy: Low Cd 2+ stress rapidly activates autophagy counteracting damage but Cd 2+ stress accrual disrupts autophagic flux and lysosomal stability, possibly resulting in lysosomal cell death. Support or Funding Information Center for Biomedical Training and Research (ZBAF) of the University of Witten/Herdecke (F.T.), Deutsche Forschungsgemeinschaft (TH345/11‐1 to F.T.), Max Kade Foundation (W.‐K.L.), CONACYT (Consejo Nacional de Ciencia y Tecnología, Mexico) (235537 to M.P.S.‐S.), and NSERC Discovery grant (E.J.P.)
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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) | 0.001 | 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) | 0.002 | 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".