Hedgehog Interacting Protein Mediates the Cross-Talk Between Endothelial Cells and Renal Proximal Tubular Cells in a Mouse Model of Renal Ischemia-Reperfusion Injury
Bibliographic record
Abstract
Background: Endothelial cells(ECs) play a vital role in the responses involved in tubular epithelial cell (TECs) damage that occurs during acute kidney injury (AKI). As abnormal hedgehog interacting protein (Hhip) expression has been linked to endothelial/epithelial-to-mesenchymal transition that appears to promote cellular remodeling in the kidney, we aimed to examine the molecular basis of Hhip-mediated crosstalk between ECs and TECs inrenal ischemia-reperfusion injury (IRI). Methods: The 10-week-old mice with Hhip knock-out (KO) both in ECs (HhipEC-KO)and in renal tubules (RT) (HhipRT-KO) and their respective controls (Hhipfl/fl) underwent 45 minutes of unilateral IRI or sham surgery along with contralateral nephrectomy. They then were followed from Day 1 to 7 post-IRI. Mouse endothelial cells (mECs) and renal proximal tubular cells (IRPTCs) with or without Hhip (siRNA) ± cisplatin (2µM) exposure were also studied in vitro. Results: Compared to sham controls, IRI-Hhipfl/fl mice developed clear AKI with high mortality rate, renal dysfunction and obvious AKI-related renal tubular cell injury, senescence and apoptosis. In contrast, such changes were significantly ameliorated in the kidneys of IRI-Hhip KO mice, particularly, less AKI-tubular injury in HhipEC-KO than HhipRT-KO mice. In vitro, naïve IRPTCs exposed to conditioned media harvested from mECs treated with cisplatin exhibited greater cellular senescence with nuclear enlargement with both mono- or multi-nuclei and increased cytoskeleton destabilization. Those changes were largely prevented in naïve IRPTCs exposed to the conditioned media harvested from Hhip KO mECs treated with cisplatin. Conclusion: Our data suggest that Hhip KO in ECs prevented or ameliorated AKI-induced renal tubular injury. This potential protection may be mediated, at least in part, by the inhibition of Hhip-mediated tubular cell senescence. Funding: Other NIH Support - Canadian Institutes of Health Research (CHIR)
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How this classification was reachedexpand
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 | 0.001 | 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 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".