397-P: Epigenetic Regulation of the Chemokine CXCL2 in Acute Kidney Injury in Diabetes
Bibliographic record
Abstract
People with diabetes are much more likely to develop acute kidney injury (AKI) than people who do not have diabetes. Here we took a reverse translational approach to identify factors that increase the risk of AKI in diabetes. Aged diabetic high fat diet-fed (DM-HFD) mice and nondiabetic controls were randomized to sham or bilateral renal ischemia reperfusion injury (IRI) surgery, with phenotyping performed 24h later. DM-HFD mice with IRI had increased plasma BUN and creatinine and increased tubule injury in comparison to either nondiabetic mice with IRI or DM-HFD mice that underwent sham surgery. NanoString nCounter analysis of AKI kidneys revealed that 47 of 248 inflammatory genes were differentially expressed in the kidneys of DM-HFD IRI mice in comparison to nondiabetic mice with IRI. The top hit was the chemokine Cxcl2, which was upregulated 2429-fold compared with sham-operated nondiabetic mice and 92-fold compared with nondiabetic mice with IRI. Urine CXCL2 excretion was increased >200-fold in DM-HFD IRI mice. By RNAscope in situ hybridization, Cxcl2 was observed to be upregulated in DM-HFD IRI kidneys, being localized primarily to infiltrating inflammatory cells, but also expressed in glomeruli and scattered tubule epithelial cells. Stimulation of bone marrow-derived macrophages (BMDMs) with lipopolysaccharide caused release of CXCL2 into the culture medium, with a significant increase in CXCL2 secretion by BMDMs from mice with myeloid cell deletion of the histone demethylase KDM6A (LysMCre+Kdma6fl/ymice). In summary, augmented AKI in aged diabetic high fat diet-fed mice is accompanied by upregulation of the myeloid cell chemoattractant CXCL2, which itself is under the influence of the histone demethylating enzyme KDM6A. The findings provide insights into the molecular causes of worsened AKI in diabetes and they illustrate that, like chronic kidney disease in diabetes, AKI processes in diabetes are also under epigenetic regulation. Disclosure S. Batchu: None. V. Yerra: None. Y. Hong: None. P. Plant: None. Y. Liu: None. A. Advani: None. Funding Canadian Institutes of Health Research (PJT166083 to A.A.)
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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) | 0.006 | 0.001 |
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".