背景:血压盐敏感性(SSBP)是心血管疾病发病率和死亡率的独立危险因素,然而病因却知之甚少。我们先前发现血清/糖皮质激素调节激酶1(SGK1)和环氧二十碳三烯酸(EET)调节上皮钠通道(ENaC)依赖性钠进入单核细胞衍生的抗原呈递细胞(APC)和NADPH氧化酶的激活,导致SSBP中isolevuglandins(IsoLGs)的形成。而醛固酮通过盐皮质激素受体(MR)激活SGK1导致高血压,我们过去的研究结果表明,血浆醛固酮水平与SSBP无关,在APC中几乎没有MR表达。因此,我们假设皮质醇通过糖皮质激素受体(GR)起作用,APC中的MR不是介导SGK1诱导SSBP的作用。
方法:我们通过测序(CITE-Seq)分析对人类外周血单核细胞进行转录组和表位的细胞索引,这些细胞使用住院患者的盐负荷/耗竭方案对SSBP进行了严格表型分析,以确定MR的表达,GR,免疫细胞中的SGK1。在额外的实验中,我们对来自单独队列的高盐体外处理后分离的人单核细胞进行了批量转录组学分析.然后我们测量了尿液和血浆皮质醇,可的松,肾素,还有醛固酮.随后,我们测量了这些激素与收缩压变化的关系,舒张压,平均动脉压和脉压以及通过IsoLG形成的免疫细胞活化。
结果:我们发现髓样APC主要表达GR和SGK1,而不表达MR。在盐敏感但非耐盐人群中,APC中GR的表达在盐负荷后增加,并随着盐消耗而减少,并且与SGK1的表达增加有关。此外,我们发现血浆和尿液皮质醇/可的松而不是醛固酮/肾素与SSBP和APCs通过IsoLGs激活相关。我们还发现皮质醇与EETs呈负相关。
结论:我们的研究结果表明,在APC中,肾脏皮质醇信号通过GR而不是MR通过皮质醇促进SSBP。尿液和血浆皮质醇可能为SSBP提供重要的当前不可用的可行诊断工具。此外,皮质醇-GR-SGK1-ENaC信号通路可能为SSBP提供治疗选择。
■什么是新的?:尽管盐敏感性是心血管疾病发病率和死亡率的主要危险因素,对血压盐敏感性(SSBP)的潜在机制知之甚少.高盐改变抗原呈递细胞(APC)中糖皮质激素受体的表达,提示糖皮质激素在SSBP中的关键作用。与盐皮质激素受体(MR)表达相比,APC中糖皮质激素受体(GR)表达升高为SSBP的GR依赖性途径提供了证据。与醛固酮治疗相比,氢化可的松治疗后体外APC中的isolevuglandins(IsoLGs)增加,表明皮质醇是这些细胞中IsoLG产生的主要驱动因素。我们的研究表明,通过皮质醇激活GR表达SGK1的机制与目前公认的SSBP发病机制不同。什么是相关的?:虽然醛固酮已被用于研究SSBP,没有考虑皮质醇是这种情况的主要驱动因素。了解影响SSBP的替代炎症途径可能提供对SSBP机制的见解,并提出一系列治疗靶标。我们的研究可能为了解和治疗盐敏感性高血压提供了一种实用的方法。临床/病理生理意义?:我们的发现坚定地支持通过SGK1表达激活SSBP的GR依赖性信号通路。皮质醇驱动机制可以为盐敏感性高血压的靶向治疗提供实用方法。此外,它可以为诊断方法铺平道路。
BACKGROUND: Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously found that serum/glucocorticoid-regulated kinase 1 (SGK1) and epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel (ENaC)-dependent sodium entry into monocyte-derived antigen-presenting cells (APCs) and activation of NADPH oxidase, leading to the formation of isolevuglandins (IsoLGs) in SSBP. Whereas aldosterone via the mineralocorticoid receptor (MR) activates SGK1 leading to hypertension, our past findings indicate that levels of plasma aldosterone do not correlate with SSBP, and there is little to no MR expression in APCs. Thus, we hypothesized that cortisol acting via the glucocorticoid receptor (GR), not the MR in APCs mediates SGK1 actions to induce SSBP.
METHODS: We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) analysis on peripheral blood mononuclear cells of humans rigorously phenotyped for SSBP using an inpatient salt loading/depletion protocol to determine expression of MR, GR, and SGK1 in immune cells. In additional experiments, we performed bulk transcriptomic analysis on isolated human monocytes following in vitro treatment with high salt from a separate cohort. We then measured urine and plasma cortisol, cortisone, renin, and aldosterone. Subsequently, we measured the association of these hormones with changes in systolic, diastolic, mean arterial pressure and pulse pressure as well as immune cell activation via IsoLG formation.
RESULTS: We found that myeloid APCs predominantly express the GR and SGK1 with no expression of the MR. Expression of the GR in APCs increased after salt loading and decreased with salt depletion in salt-sensitive but not salt-resistant people and was associated with increased expression of SGK1. Moreover, we found that plasma and urine cortisol/cortisone but not aldosterone/renin correlated with SSBP and APCs activation via IsoLGs. We also found that cortisol negatively correlates with EETs.
CONCLUSIONS: Our findings suggest that renal cortisol signaling via the GR but not the MR in APCs contributes to SSBP via cortisol. Urine and plasma cortisol may provide an important currently unavailable feasible diagnostic tool for SSBP. Moreover, cortisol-GR-SGK1-ENaC signaling pathway may provide treatment options for SSBP.