Investigating Hepatocyte Nuclear Factor 4 Alpha as a Central Regulator of Kidney Graft Repair
Bibliographic record
Abstract
Background: Kidney transplantation is the optimal treatment for end-stage kidney disease. However, ischemia-reperfusion injury (IRI) harms all transplanted kidneys, limiting their short- and long-term survival. Previously, we determined that superior kidney function/structure after IRI is associated with preserved expression of mitochondrial proteins during normothermic ex vivo kidney perfusion (NEVKP). We identified a potential transcriptional regulator of these mitochondrial proteins, hepatocyte nuclear factor 4a (HNF4A), which may present a novel target for kidney repair. Our goal is to determine whether a novel HNF4A agonist, N-trans caffeoyltyramine (NCT), protects kidneys from IRI. We will evaluate the effectiveness of NCT treatment in vitro studying male and female primary proximal tubular cells (PTECs), and in vivo studying male and female mice. Methods: First, we inhibited HNF4A in primary male and female PTECs, using a pharmacologic or genetic approach. We then assessed gene expression, cell death and mitochondrial function. Next, we treated PTECs with NCT/vehicle and examined cell death and expression of HNF4A target genes. Lastly, male and female mice were subjected to bilateral IRI, and kidney function and structure were assessed on post-operative day 2 and 14. Results: HNF4A inhibition in vitro increased PTEC death and decreased mitochondrial function, while NCT increased the expression of HNF4A and mitochondrial genes, suggesting that NCT may be protective. We developed a sex-specific model of bilateral IRI and demonstrated that warm ischemia (27-minutes in males, 40-minutes in females) impairs kidney function on post-operative day 2, indicated by elevated serum creatinine and tubular injury. Mice also developed tubulointerstitial fibrosis on post-operative day 14. Conclusion: Based on the preliminary results, HNF4A is important for the metabolic function and viability of PTECs. We will next administer NCT to mice prior to IRI and examine whether HNF4A agonist preserves mitochondria and improves kidney function and structure.
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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) | 0.000 | 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) | 0.001 | 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".