Improved Renal Function by Eta Receptor Blockade Is Associated with Reduced Renal Expression of Tgfβ and B FGF and Increased Activity of Mmp-2 in Shrsp
Bibliographic record
Abstract
P104 Endothelin-1 (ET-1) receptor antagonists increase life span and improve renal function in salt-loaded stroke prone SHR (SHRSP). Mechanisms underlying these ET-1-dependent processes are unclear. We hypothesized that ET-1 induces renal damage by increasing expression of growth/inflammatory factors, important in renal fibrosis. Male 8 week-old SHRSP (n=24) were randomized in 3 groups: control group; high salt diet (4% NaCl) and salt diet plus an ET A receptor antagonist, BMS 182874 (40 mg/Kg/day). Systolic blood pressure (SBP) was measured weekly and renal function assessed 2 weekly. After 20 weeks treatment, rats were killed. Expression of renal ET-1 and ET A /ET B receptor mRNA was evaluated by RT-PCR, renal expression of transforming growth factor β1 (TGF-β1) and basic fibroblast growth factor (bFGF) were determined by Western blot and, metalloproteinase (MMP-2) activity was measured by gelatine-enzymography. SBP increased to ∼ 240 mmHg in salt-loaded rats. BMS treatment had a small, but significant BP lowering effect and delayed progression and severity of renal dysfunction. In salt-loaded SHRSP renal ET-1 mRNA expression was increased (1.6±0.1vs control 1±0.1; p<0.05), and ET A receptor mRNA expression was decreased (0.7±0.1 vs control 1±0.1; p<0.05). ET B subtype mRNA expression was unchanged. BMS treatment did not reverse these changes. Salt-loaded SHRSP exhibited increased renal expression of TGF-β1 (10.4±1SL-SHRSP vs 1±0.4 control, p<0.05) but not of bFGF (1.2±0.1 vs control 1±0.02) and augmented activity of MMP-2 (4.8±1.6 vs control 1±0.3, p<0.05). Treatment with BMS decreased expression of both TGF-β1 (6±0.4, p<0.05) and bFGF (0.6±0.1, p<0.05), and reduced MMP-2 activity (0.3±0.1). These data suggest that severe hypertension and renal dysfunction in salt-loaded SHRSP is associated with increased expression of renal ET-1 and growth factors. These effects were ameliorated by BMS treatment. In conclusion, nephroprotection by ET A receptor blockade may be mediated, in part, by normalizing expression of growth factors and restoring MMP2 activity in experimental models of severe hypertension.
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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 | 0.000 |
| 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 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".