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.

中文翻译：

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树突状细胞盐皮质激素受体通过调节辅助性 T 17 分化来控制血压：Plcβ1/4–Stat5–NF-κB 通路的作用


背景和目的树突状细胞 （DC） 与血压 （BP） 调节密切相关。盐皮质激素受体 （MR） 是抗高血压治疗的重要药物靶点。然而，DC MR 在高血压发病机制中的作用尚未完全阐明。本研究旨在确定 DC MR 在 BP 调节中的作用并探讨其机制。方法 收集高血压患者 （HTN） 的肾活检和外周血标本进行免疫染色和流式细胞术。向树突状细胞 MR 敲除 （DCMRKO） 小鼠、DC MR 过表达 （DCMROV） 小鼠、DCMROV/IL-17A 敲除 （DCMROV/IL-17AKO） 小鼠和非利酮处理的 C57BL/6 小鼠输注血管紧张素 II （Ang II） 建立高血压模型。使用 western blotting、染色质免疫沉淀、免疫共沉淀和体内 DC 去除或过继转移来描述 DC MR 在高血压发展中的功能重要性。结果 盐皮质激素受体拮抗剂 （螺内酯和非奈利酮） 抑制 HTN 和小鼠的 DC 聚集和激活，以及高血压。与同窝对照 （LC） 小鼠相比，树突状细胞 MR 敲除小鼠在输注 Ang II 后血压显著降低，靶器官损伤减轻。流式细胞术显示，DC MR 缺陷减轻了 Ang II 诱导的 DC 活化和辅助性 T 细胞 17 （Th17） 细胞分化。RNA 测序显示，MR 缺陷型 DC 的 Plcβ 1 和 Plcβ 4 表达升高，敲低其逆转了 MR 缺陷对 DC 激活和 Th17 分化的抑制作用。MR 缺陷型 DC 的过继转移保护了 Ang II 诱导的高血压，而敲除 Plcβ 1/4 消除了保护作用。 在分子水平上，MR 负调控 Plcβ1/4，后者募集 SHP-1 以灭活 Stat5 活性，导致 NF-κB 活化和 Th17 极化增强。此外，DCMROV 小鼠在输注 Ang II 后表现出比对照小鼠更多的血压升高和靶器官损伤，这些差异在 DCMROV/IL-17AKO 小鼠中被消除。最后，MR 拮抗剂降低了 HTN 和小鼠中 Th17 的聚集。结论 树突状细胞 MR 通过调节 Plcβ1/4–Stat5–NF-κB 信号传导调节 Th17，在高血压发病机制中发挥重要作用，阻断 DC MR 有利于治疗高血压。