#2328 Exploring the role of KDM6A as a regulator of proximal tubular epithelial cell dysmetabolism in diabetic kidney disease
Bibliographic record
Abstract
Abstract Background and Aims Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and progresses faster in males. In DKD, proximal tubular epithelial cells (PTECs) increase the breakdown of glucose (via glycolysis) and glutamine for utilization in the TCA cycle, the major energy-producing mechanism. This shift leads to the accumulation of pathogenic products, such as lactate, thus promoting DKD. Epigenetics partly mediates metabolic alterations in DKD. KDM6A is a histone demethylase that erases the repressive mark H3K27me3 at DNA promoters, resulting in upregulation of many target genes. These include metabolic and inflammation genes increased in DKD. High levels of KDM6A were found in mouse and human diabetic kidneys, and in PTECs exposed to high glucose. Loss of KDM6A in podocytes attenuated glomerular lesions in mice with DKD, however, the effect of targeting this enzyme in PTECs in DKD remains unknown. We aim to determine, in a sex-specific fashion, the role of KDM6A in mediating PTEC dysmetabolism under high glucose. Method Human PTECs of a male or a female donor were subjected to siRNA-mediated KDM6A inhibition for 48 h, then treated them with normal glucose (5.5 mM), high glucose (25 mM), or osmotic control (5.5 mM glucose + 19.5 mM mannitol) for 24 h. Results Male-derived PTECs displayed significantly higher levels of extracellular lactate than female PTECs (P < 0.05). High glucose treatment significantly increased lactate secretion in male PTECs, an effect that was only modest in female PTECs. Silencing of KDM6A reduced lactate secretion in both sexes, regardless of the glucose concentration. At the gene level, high glucose significantly increased the expression of LDHA and MDH2 (enzymes involved in glycolysis and the TCA cycle, respectively) in male, but not female PTECs, and this effect was prevented by KDM6A inhibition. Conclusion Our findings suggest that KDM6A mediates alterations in glucose and glutamine metabolism induced by high glucose in male PTECs. This work has the potential to establish KDM6A as a novel clinical target in DKD.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.014 | 0.004 |
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".