Loss of receptor interacting protein kinases 3 and caspase‐8 augments intrinsic apoptosis in tubular epithelial cell and promote kidney ischaemia‐reperfusion injury
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Bibliographic record
Abstract
ABSTRACT Background Ischaemia‐reperfusion injury (IRI) is associated with programmed cell death that promotes inflammation and organ dysfunction. Necroptosis is mediated by members of receptor interacting protein kinases (RIPK1/3). Inhibition of RIPK1/3 provides a pro‐survival benefit in kidney IRI. Caspase‐8 initiates apoptosis and contributes to IRI. We studied whether inhibiting both RIPK3 and caspase‐8 would provide an additional benefit in kidney IRI. Methods A clamp was applied to the left kidney pedicle for 45 min followed by right kidney nephrectomy. Kidney and serum from wild type, RIPK3 −/− , and RIPK3 −/− caspase‐8 −/− double knockout (DKO) mice were collected post‐IRI for assessment of injury. Tubular epithelial cells (TEC) isolated from wild type, RIPK3 −/− , and DKO mice were treated with interferons‐γ and interleukin‐1β to induce apoptotic death. Results Kidney IRI of DKO mice did not show improvement over RIPK3 −/− mice. We have found that DKO triggered ‘intrinsic’ apoptosis in TEC in response to interleukin‐1β and interferons‐γ. Up‐regulation of the B‐cell lymphoma 2 (Bcl‐2)‐associated death promoter, the Bcl‐2‐homologous antagonist killer and Bcl‐2‐associated X protein and enhanced activation of caspase‐3 and 9 were found in DKO TEC. TEC infected with Murine cytomegalovirus that encodes multiple cell death inhibitors resist to death. Conclusion We show that the deletion of both RIPK3 and caspase‐8 does not provide additive benefit in IRI or TEC death and may enhance injury by up‐regulation of intrinsic apoptosis. This suggests blocking multiple death pathways may be required for the prevention of kidney IRI clinically.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 it