Biphasic actions of the adenosine A2a receptor antagonist istradefylline in mice with obstructive uropathy
Bibliographic record
Abstract
Regardless of its underlying causes, progressive chronic kidney disease is characterized by progressive kidney fibrosis. The adenosine A2a receptor is expressed by activated kidney fibroblasts. Istradefylline is an adenosine A2a receptor antagonist that has received regulatory authority approval as add-on treatment of Parkinson's disease. Here, we examined the potential of repurposing istradefylline for kidney disease by administering istradefylline to mice with kidney fibrosis caused by unilateral ureteral obstruction (UUO). C57BL/6N mice underwent sham or UUO surgery and were followed for 14 days. Mice were treated with vehicle or istradefylline, with istradefylline initiated either the day after surgery (early intervention) or seven days after surgery (late intervention). Early intervention with istradefylline increased mortality in UUO mice and upregulated the expression of some inflammatory genes. In contrast, late intervention with istradefylline attenuated upregulation of the profibrotic cytokine Il11 and of extracellular matrix proteins in UUO kidneys. Istradefylline similarly attenuated transforming growth factor-β1 induced upregulation of Il11, Col1a1 and Fn1 in NRK-49F fibroblasts. The adenosine A2a receptor has both anti-inflammatory and profibrotic effects. The therapeutic window by which adenosine A2a receptor antagonism may slow CKD progression is thus relatively narrow, even when employing an agent with immediate clinical applicability.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".