Autophagy Inhibition Aggravates Renal Microvascular Injury Secondary to Ischemia-Reperfusion
Bibliographic record
Abstract
Background: Ischemia-reperfusion injury (IRI) is an integral component of kidney transplantation. Programmed cell death (PCD) of endothelial cells (EC) in peritubular capillaries (PTCs) post-IRI is a major predictor of long-term loss of renal function. We have shown that caspase-3-deficient mice show reduced PTC apoptosis post-IRI and preserved long-term renal function. Autophagy is a cellular stress response that protects against PCD. However, the precise role of PTC autophagy post-IRI remains unclear. Here, we characterize the dynamics of PCD activation and the effect of autophagy inhibition on the renal microvasculature post-IRI. Methods: Transgenic GFP-LC3 mice were subjected to unilateral renal artery clamping for 30 minutes with contralateral nephrectomy. Mice were injected intraperitoneally with PBS or chloroquine (CHQ), an autophagy inhibitor, on the day of surgery and every day post-surgery until sacrifice. Mice were sacrificed 1, 2, 7, or 21 days post-IRI. Kidney function was assessed by measuring serum creatinine levels. Activation of Caspase-3-dependent apoptosis and necroptosis (pRIPK3) were measured by immunohistochemistry (IHC). Autophagy activation was evaluated by confocal immunofluorescence microscopy for GFP-LC3 puncta. PTC rarefaction, myofibroblast accumulation, and collagen deposition were assessed. Results: IRI induced a specific pattern of apoptosis, necroptosis, and autophagy in PTCs. PTCs showed sustained apoptosis from day 1 to day 21 post-IRI, whereas necroptosis showed an early increase at days 1 and 2 with a rapid return to basal level at day 7. GFP-LC3+ autophagy puncta increased steadily until day 21 in PTCs. CHQ inhibited autophagic flux in PTC and worsened renal function with higher serum creatinine levels post-IRI 1 day. In the long term (21 days), microvascular rarefaction was significantly increased in the CHQ-injected group compared to the vehicle-treated group. This was associated with increased renal fibrosis, increased α-SMA, and collagen deposition within the PTC. Conclusions: The results indicate that IRI induces progressive autophagy activation in PTC EC. Inhibition of autophagy aggravates renal dysfunction and increases microvascular injury, myofibroblast differentiation, and collagen deposition post-IRI. Funding: 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) | 0.000 | 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 | 0.001 |
| 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".