Caspase-3 Activation Increases with Age and Aggravates Kidney Injury After Ischemia-Reperfusion
Bibliographic record
Abstract
Background: Rarefaction of peritubular capillaries (PTC) after ischemiareperfusion injury (IRI) predicts progressive renal failure, especially in older kidneys. We previously demonstrated the importance of caspase-3-dependent microvascular damage in progressive kidney dysfunction after IRI. We also showed that renal IRI increases circulating levels of ApoExo; an immunogenic type of exosome-like vesicles produced by apoptotic endothelial cells downstream of caspase-3 activation, and characterized by the presence of LG3/perlecan autoantigen and active 20S proteasome. Here, we hypothesize that age modulates caspase-3 activation after renal IRI leading to increased release of ApoExo, enhanced PTC rarefaction, fibrosis and renal dysfunction. Methods: Unilateral renal pedicle clamping (30 minutes) and contralateral nephrectomy were performed in young (8 weeks-old) and old (27 and 53 weeks-old) mice. ApoExo were purified from serum-free medium conditioned by apoptotic murine endothelial cells in vitro and injected to mice via tail vein every other day. Endpoints were assessed 21 days post-IRI. ApoExo circulating levels were measured by proteasome activity and anti-LG3 titers by ELISA. Complement deposition, caspase-3 activation, PTC rarefaction and fibrosis were assessed by immunohistochemistry. Renal function was monitored by BUN level. Results: At baseline, old mice showed higher levels of caspase-3 activation within PTC, lower PTC density and higher anti-LG3 titers. Renal IRI led to significant increase in PTC caspase-3 activation, ApoExo and anti-LG3 circulating levels with age. PTC C4d deposition, interstitial fibrosis and renal function were worsened by age. To test the role of ApoExo in fueling maladaptive responses to IRI, young mice were injected with ApoExo to reach circulating levels observed in old mice. ApoExo injection increased anti-LG3 formation, PTC C4d deposition, caspase-3 activation, PTC rarefaction and interstitial fibrosis, and aggravated renal dysfunction. Conclusions: Our results suggest that caspase-3 activation within PTC increases with older age leading to more ApoExo production post-IRI. The latter enhances microvascular damage and fibrosis, favoring progressive kidney dysfunction. Funding: Private Foundation Support, 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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".