BACKGROUND Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP. METHODS We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c+ JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney's immune cells and cytokine levels. Echocardiography was performed to assess cardiac function. RESULTS We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c+ APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha). CONCLUSIONS Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

中文翻译：

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髓系特异性 JAK2 导致血压的炎症和盐敏感性。


背景 血压的盐敏感性 （SSBP） 以血压急剧变化为特征，膳食钠摄入量发生变化，是高血压患者和非高血压患者心血管疾病和死亡的独立危险因素。我们之前发现钠浓度升高会激活抗原呈递细胞 （APC），导致高血压，但机制尚不清楚。在这里，我们假设 APC 特异性 JAK2 （Janus 激酶 2） 通过 STAT3 （信号转导和转录激活因子 3） 和 SMAD3 （针对 decapentaplegic 同源物 3 的小母亲） 导致 SSBP。方法 我们在体外单核细胞暴露于高盐和体内高钠处理后进行大量或单细胞转录组学分析，使用严格的载盐/耗竭方案对 SSBP 进行表型。我们还使用了骨髓细胞特异性 CD11c+ JAK2 敲除小鼠模型，并在 N-omega-硝基-L-精氨酸-甲酯和高盐饮食处理后通过放射遥测测量血压。我们使用流式细胞术进行免疫表型分析和测量细胞因子水平。进行荧光原位杂交和免疫组化，以在空间上可视化肾脏的免疫细胞和细胞因子水平。进行超声心动图评估心脏功能。结果我们发现，高盐处理上调人单核细胞中 JAK/STAT/SMAD 通路的基因表达，同时下调该通路的抑制剂，例如抑制细胞因子信号传导和细胞因子诱导的 SH2。JAK2 通路基因的表达反映了盐敏感但不耐盐的人类在盐负荷和耗竭后血压的变化。 JAK2 消融，特别是在 CD11c+ APC 中，减轻了 SSBP 小鼠盐诱导的高血压。从机制上讲，我们发现 SMAD3 在 JAK2 和 STAT3 的下游起作用，导致肾脏 APC 中高反应性异亮兰素和促炎细胞因子 IL（白细胞介素）-6 的产生增加，从而激活 T 细胞并增加 IL-17A、IL-6 和 TNF-α （肿瘤坏死因子-α） 的产生。结论 我们的研究结果揭示了 APC JAK2 信号通路是人类 SSBP 诊断和治疗的潜在靶点。