Department of Medicine, Division of Clinical Pharmacology (M.S., L.A.A., A.L.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.), Vanderbilt University Medical Center, Nashville, TN.
Department of Medicine, Division of Genetic Medicine (C.B., E.R.G.), Vanderbilt University Medical Center, Nashville, TN.
Circ Res. 2024 Oct 11;135(9):890-909. doi: 10.1161/CIRCRESAHA.124.323595. Epub 2024 Sep 12.
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.
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.
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).
Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.
血压的盐敏感性（SSBP）的特征是随着膳食钠摄入量的变化血压急性变化，是高血压和非高血压人群心血管疾病和死亡率的独立危险因素。我们之前发现，升高的钠浓度激活抗原呈递细胞（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（小母亲对抗 decapentaplegic 同源物 3）有助于 SSBP。
我们使用严格的盐加载/耗尽方案对 SSBP 进行表型分析，对体外暴露于高盐的单核细胞和体内高钠处理的人进行了批量或单细胞转录组分析。我们还使用了髓样细胞特异性 CD11c JAK2 敲除小鼠模型，并在 N-ω-硝基-L-精氨酸甲酯和高盐饮食治疗后使用无线电遥测测量血压。我们使用流式细胞术进行免疫表型分析和细胞因子水平测量。荧光原位杂交和免疫组织化学用于空间可视化肾脏的免疫细胞和细胞因子水平。超声心动图用于评估心脏功能。
我们发现，高盐处理上调了人单核细胞中 JAK/STAT/SMAD 通路的基因表达，同时下调了该通路的抑制剂，如抑制细胞因子信号和细胞因子诱导的 SH2。盐敏感但不盐抵抗的人中，盐负荷和耗尽后血压的变化与 JAK2 通路基因的表达相吻合。在具有 SSBP 的小鼠中，特异性在 CD11c APC 中敲除 JAK2，可减轻盐诱导的高血压。从机制上讲，我们发现 SMAD3 是 JAK2 和 STAT3 的下游，导致肾脏 APC 中高度反应性异亮谷胱甘肽和促炎细胞因子 IL（白细胞介素）-6 的产生增加，激活 T 细胞并增加产生 IL-17A、IL-6 和 TNF-α（肿瘤坏死因子-α）。
我们的发现揭示了 APC JAK2 信号通路作为人类 SSBP 诊断和治疗的潜在靶点。
