Abstract 065: Induction of Human Endothelin-1 Overexpression for 3 Months Causes Blood Pressure Rise and Renal Injury
Bibliographic record
Abstract
Introduction: Endothelium-derived endothelin (ET)-1 has been implicated in hypertension and renal disease but the mechanisms are complex and remain unclear. We have shown that tamoxifen-inducible endothelium-restricted human ET-1 overexpressing (ieET-1) mice exhibited BP rise after 3 weeks of induction in an ET type A receptor (ET A R)-dependent manner, in absence of renal injury. It is unknown whether long-term exposure to ET-1 overexpression results in sustained BP elevation and renal injury. Methods: Adult male ieET-1 and control tamoxifen-inducible endothelium-restricted Cre recombinase (ieCre) mice were treated with tamoxifen (1 mg/kg/day, SC) for 5 days and 2.5 months later were treated or not with an ET A R blocker, atrasentan (10 mg/kg/day, PO) for 2 weeks. Blood pressure (BP) by telemetry, renal artery flow (RAF) by ultrasonography, immune cell infiltration by flow cytometry, kidney injury molecule (KIM)-1 expression by immunofluorescence, 24h urinary albumin by ELISA and creatinine by alkaline picrate method were determined at the end of the study. Results: Induction of ET-1 overexpression for 3 months resulted in greater systolic BP (135±4 vs 114±2 mmHg, P <0.001) and reduced RAF (1.7±0.2 vs 3±0.3 mL/min, P <0.05). ieET-1 mice presented increased myeloid (21255±5294 vs 5146±1987 CD11b + cells/kidney, P <0.001) and myeloid-derived suppressor cells (5332±1463 vs 1126±507 CD11b + Gr-1 + cells/kidney, P <0.01) renal infiltration associated with greater frequency of CD11b + (23.2±1.8 vs 7.5±1.6 % of CD45 + cells, P <0.001) and non-immune renal cells (CD45 - , 5.7±0.8 vs 3.2±0.6 % of CD45 - cells, P <0.001) expressing a pro-inflammatory maker, CD36. Early renal injury was demonstrated in ieET-1 by increased KIM-1 expression in proximal tubules (4.0±0.7 vs 1.0±0.2 % of renal cortex, P <0.05) and unchanged albumin/creatinine ratio (327±74 vs 173±36 μg/mg, P=0.215). Atrasentan reversed or reduced all of the above except the decreased RAF ( P <0.05). Conclusions: Long-term exposure to endothelial ET-1 overexpression caused sustained BP elevation and renal injury via ET A R.
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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) | 0.001 | 0.001 |
| 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".