Pharmacological PAR‐1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy
Bibliographic record
Abstract
ABSTRACT Vorapaxar‐dependent protease‐activated receptor (PAR)‐1 inhibition diminishes diabetic nephropathy in experimental type 1 diabetes. As most patients with diabetic nephropathy suffer from type 2 diabetes, the aim of this study was to investigate whether PAR‐1 inhibition also limits diabetic nephropathy in experimental type 2 diabetes. Consequently, leptin‐deficient black and tan brachyuric (BTBR ob/ob ) mice were randomly assigned to vorapaxar (1.75 mg/kg; twice weekly via oral gavage) or vehicle treatment, whereas matched wild‐type (WT) BTBR (BTBR WT ) mice served as nondiabetic controls. Weight and (non‐fasting) blood glucose levels were monitored for up to 18 wk, after which kidney function and histologic damage was evaluated postmortem. We show that blood glucose levels and body weight increased in diabetic BTBR ob/ob mice compared with nondiabetic BTBR WT controls. Vorapaxar‐dependent PAR‐1 inhibition reduced but did not normalize blood glucose levels in BTBR ob/ob mice, whereas it potentiated the increase in body weight. Vorapaxar did not, however, preserve kidney function, whereas it only minimally reduced histopathological signs of kidney injury. Overall, we thus show that PAR‐1 inhibition reduces blood glucose levels during the progression of diabetic nephropathy in experimental type 2 diabetes but does not improve renal function. This is in contrast to the therapeutic potential of vorapaxar in type 1 diabetes‐induced nephropathy, highlighting the importance of disease‐dependent treatment modalities.—Waasdorp, M., Florquin, S., Duitman, J., Spek, C. A. Pharmacological PAR‐1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy. FASEB J. 33, 10966–10972 (2019). www.fasebj.org
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".