Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Department of Cardiology, Hospital of Southwest Jutland, Esbjerg, Denmark.
Am J Physiol Renal Physiol. 2024 Jul 1;327(1):F37-F48. doi: 10.1152/ajprenal.00268.2023. Epub 2024 May 23.
Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1β, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: ) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension ( = 69, amiloride 5-10 mg/day for 8 wk) and ) patients with hypertension and type 1 diabetes mellitus (T1DM) ( = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1β. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages. ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.
白细胞介素（IL）-17A 有助于临床前模型中的高血压。T 辅助 17 和树突状细胞被 NaCl 激活，这可能涉及上皮钠通道（ENaC）。我们假设 ENaC 阻滞剂阿米洛利可降低高血压患者的血浆 IL-17A 和相关细胞因子。在接受阿米洛利治疗前后，通过免疫测定法测定了来自两个患者队列的血浆中 IL-17A、IFN-γ、TNF、IL-6、IL-1β 和 IL-10 的浓度：）患有 2 型糖尿病（T2DM）和治疗抵抗性高血压的患者（=69，阿米洛利 5-10mg/天，8 周）和）患有高血压和 1 型糖尿病（T1DM）的患者（=29，在标准盐摄入量下）（阿米洛利 20-40mg/天，2 天）。分析了接受阿米洛利（2mg/kg/天，4 天）治疗的患有 T1DM 的 ANG II 高血压小鼠的血浆和组织。在体外确定了阿米洛利和苯甲脒对巨噬细胞细胞因子的影响。与 T1DM 相比，患有 T2DM 的患者的血浆细胞因子浓度更高（IL-17A 约 40 倍）。在患有 T2DM 的患者中，阿米洛利对 IL-17A 没有影响，但降低了 TNF 和 IL-6。在患有 T1DM 的患者中，阿米洛利对 IL-17A 没有影响，但增加了 TNF。在两个队列中，血压下降和血浆 K+增加与血浆细胞因子变化无关。在小鼠中，阿米洛利对血浆、肾脏、主动脉或左心室内的 IL-17A 没有影响，但增加了心脏和肾脏组织中的 TNF。在脂多糖刺激的人 THP-1 巨噬细胞中，阿米洛利和苯甲脒（从 1nmol/L）降低了 TNF、IL-6、IL-10 和 IL-1β。总之，阿米洛利抑制 ENaC 可降低 2 型糖尿病患者的促炎细胞因子 TNF 和 IL-6，但不降低 IL-17A，可能通过直接作用于巨噬细胞。ENaC 活性可能有助于巨噬细胞来源的细胞因子释放，因为阿米洛利通过抑制 TNF 和 IL-6 细胞因子在耐药性高血压和 2 型糖尿病患者以及体外 THP-1 衍生的巨噬细胞中发挥抗炎作用。
