Abstract 11704: NF-κβ Signaling Regulates Vasopressin Receptor 2 Promoter Activity
Bibliographic record
Abstract
Background: Arginine vasopressin, through vasopressin receptor 2 (AVP-V2R), regulates water reabsorption via aquaporin-2 and sodium reabsorption via several mechanisms. We recently implicated V2R, and its transcriptional downregulation, in a model of B-cell deficiency with increased sodium- and water-excretion and reduced blood pressure (BP). Here, we identify mechanisms underlying the immunoregulation of V2R transcription and evaluate the importance of V2R in BP regulation. Methods & Results: Using an Avpr2 promoter-luciferase reporter in an immortalized mouse inner medullary collecting duct cell line [mIMCD-3], we found that IL-6 (100ng/mL), a stimulator of NF-κβ signaling, increased promoter-reporter activity (10.4±3.2 vs 4.0±0.5 RLU; N=2-3/group); while PDTC (60μM), an inhibitor of NF-κβ signaling, reduced promoter-reporter activity (2.2 vs 4.0±0.5 RLU; N=1-3/group). Importantly, single point mutations in two putative NF-κβ binding sites in the proximal Avpr2 promoter also reduced promoter activity (2.3±0.6 vs 4.0±0.5 RLU; N=2-3/group), and blocked the stimulatory effect of IL-6 (2.4 vs 2.3±0.6 RLU; N=1-2/group). An anti-IL-6 receptor antibody (10μg/mL vs isotype, 10μg/mL) also abolished the stimulatory effect of IL-6 on promoter activity (3.2 vs 9.1 RLU; N=1/group). To determine the role of V2R in BP regulation, wild-type C57BL/6J mice (male and female; aged 10-wk) were randomized to (i) Tolvaptan (TOL), a selective V2R-antagonist or (ii) DMSO/glycerol control (50/50) via osmotic mini-pump (0.0375mg/d). Invasive hemodynamics 12-d post-implant revealed reduced mean arterial pressure (MAP) in TOL-treated mice (76±3 vs 86±3 mmHg; N=4-5/group; P<0.05), while metabolic cage studies 8-11-d post-implant showed higher 24-h urine volume/body weight (UV/BW; 0.07±0.00 vs 0.05±0.00 mL/g; N=4-5/group; P<0.05) and 24-h sodium excretion/BW (0.25±0.01 vs 0.17±0.01 mg/d/g; N=4-5/group; P<0.01). Correlation analyses revealed inverse relationships between MAP and 24-h UV/BW (r=-0.65; N=9 pairs; P<0.05) and 24-h sodium excretion/BW (r=-0.64; N=9 pairs; P<0.05). Conclusion: These studies suggest that the V2R promoter is responsive to NF-κβ signaling, and that V2R serves a role in BP homeostasis through sodium- and water-handling.
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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 | 0.000 | 0.001 |
| 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) | 0.001 | 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 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".