Dendritic cell mineralocorticoid receptor controls blood pressure by regulating T helper 17 differentiation: role of the Plcβ1/4–Stat5–NF-κB pathway
Bibliographic record
Abstract
BACKGROUND AND AIMS: Dendritic cells (DCs) are closely related to blood pressure (BP) regulation. Mineralocorticoid receptor (MR) is an important drug target for antihypertensive treatment. However, the role of DC MR in the pathogenesis of hypertension has not been fully elucidated. This study aimed to determine the role of DC MR in BP regulation and to explore the mechanism. METHODS: Renal biopsy and peripheral blood samples were collected from hypertensive patients (HTN) for immunostaining and flow cytometry. Dendritic cell MR knockout (DCMRKO) mice, DC MR overexpressing (DCMROV) mice, DCMROV/IL-17A knockout (DCMROV/IL-17AKO) mice and finerenone-treated C57BL/6 mice were infused with angiotensin II (Ang II) to establish hypertensive models. Western blotting, chromatin immunoprecipitation, co-immunoprecipitation, and in vivo DC depletion or adoptive transfer were used to delineate the functional importance of DC MR in hypertension development. RESULTS: Mineralocorticoid receptor antagonists (spironolactone and finerenone) suppressed DC aggregation and activation, as well as hypertension in HTN and mice. Compared with littermate control (LC) mice, dendritic cell MR knockout mice had strikingly decreased BPs and attenuated target organ damage after Ang II infusion. Flow cytometry showed that DC MR deficiency mitigated Ang II-induced DC activation and T helper 17 (Th17) cell differentiation. RNA sequencing revealed that MR-deficient DCs had elevated expression of Plcβ1 and Plcβ4, knockdown of which reversed the inhibitory effect of MR deficiency on DC activation and Th17 differentiation. Adoptive transfer of MR-deficient DCs protected Ang II-induced hypertension, whereas knockdown of Plcβ1/4 eliminated the protective effects. At the molecular level, MR negatively regulated Plcβ1/4, which recruited SHP-1 to inactivate of Stat5 activity, resulting in enhanced NF-κB activation and Th17 polarization. Furthermore, DCMROV mice manifested more elevated BPs and target organ damage than control mice after Ang II infusion, and these differences were abolished in DCMROV/IL-17AKO mice. Finally, MR antagonists decreased the aggregation of Th17 in HTN and mice. CONCLUSIONS: Dendritic cell MR plays important roles in the pathogenesis of hypertension by regulating Th17 through Plcβ1/4-Stat5-NF-κB signalling, and blockade of DC MR is beneficial for treating 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) | 0.000 | 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 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".