Hedgehog Interacting Protein (Hhip) Deficiency in Endothelial Cells Prevents Ischemia Reperfusion-Induced Renal Tubular Cell Injury Through Inhibition of NF-KB Signaling
Bibliographic record
Abstract
Background: Acute kidney injury (AKI) caused by renal ischemia reperfusion (R I/R) is a major clinical issue that is lacking viable therapies, and its underlying mechanisms are poorly understood. Given the important role of hedgehog interacting protein in chronic kidney disease-related renal fibrosis, we investigated whether Hhip knockout in endothelial cells (EC) (HhipEC KO) could prevent R I/R-induced kidney injury in vivo and in vitro. Methods: Male HhipEC KO and control Hhipfl/fl mice at 10-weeks old were subjected to 45 minutes of the unilateral R I/R or sham surgery, both with contralateral nephrectomy. The AKI time-course was examined at Day1, Day 3, Day7 and Day 21. In vitro, naïve renal proximal tubular cells (IRPTCs) exposed to the conditioned media harvested from mouse endothelial cell (mECs) with or without Hhip (siRNA) ± gentamicin treatment, were studied. Results: Compared to the respective controls, R I/R mice (Hhipfl/fl and HhipEC KO) body weight loss (BW, g) occurred from Day 1 until Day 21, regardless of Hhip deficiency. In line with the AKI time course, Hhipfi/fl-R I/R mice displayed kidney dysfunction marked by increased urinary albumin-to-creatinine ratio; tubular/endothelial cell injury and fibrosis as assessed by kidney morphological staining (Periodic Acid-Schiff, Masson's trichrome and Sirius Red) with enhanced cystatin C-, kidney-induced molecular 1-and TGFβ1- immunoexpression in their kidneys. Maladaptive and inadequate renal tubular damage repair was observed by enhanced vascular cell adhesion protein 1 and NF/kB (p50/p65) expression. In contrast, these changes were significantly ameliorated in the kidneys of HhipEC KO -R I/R mice. In vitro, naïve IRPTCs exposed to the conditioned media harvested from mECs treated with gentamicin (2.5mg/ml) had lower wound healing ability/capacity, higher cellular senescent activity and increased NF/kB expression. Those changes were largely prevented in naïve IRPTCs exposed to conditioned media harvested from Hhip KO mECs treated with gentamicin. Conclusions: Our data suggest that Hhip knockout in endothelial cells prevented AKI-induced renal tubular injury. This action might be mediated, at least, in part, by inhibition of NF-KB signaling. Funding: Government Support - Non-U.S.
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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 | 0.000 |
| 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 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".