Majid Dewan Syed Abdul, Castillo Alexander
Department of Physiology, Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana, United States.
Am J Physiol Regul Integr Comp Physiol. 2025 Jul 1;329(1):R216-R224. doi: 10.1152/ajpregu.00253.2024. Epub 2025 Jun 14.
Tumor necrosis factor-α (TNF-α) exerts natriuresis via activation of its receptor type 1 in the kidney. Although chronic high salt (HS) intake produces this cytokine by immune activation of the mononuclear phagocyte cells, it has not yet been examined whether acute salt loading produces this cytokine and can induce consequent natriuresis. Here, we measured the changes in plasma level and urinary excretion rate of TNF-α (UV) during intravenous infusion of isotonic saline (0.9% NaCl), first at euvolemic conditions (3 µL/min for 60 min; baseline period) and then at an enhanced infusion rate (12 µL/min for 90 min; salt-loading period) in control mice ( = 7) and TNF-α inactivator, etanercept (ETN; 0.5 mg/kg ip once daily for 3 days before the experiment day; = 7) treated mice. TNF-α concentration in samples was determined using an enzyme-linked immunosorbent assay (ELISA) kit (Bioscience, Woburn, MA). During baseline period, TNF-α level in plasma was undetected, but it increased during the salt-loading period in both control (3.7 ± 1.3 pg/mL) and ETN-treated (3.3 ± 1.2 pg/mL) mice. In control mice, the baseline UV was minimal (0.01 ± 0.002 pg/min/g) but increased to 0.1 ± 0.03 pg/min/g ( < 0.05) with associated increase in urinary sodium excretion (UV; 0.5 ± 0.2 to 4.8 ± 1.2 µmol/min/g; < 0.05) during salt-loading period. In ETN-treated mice, both the UV (0.01 ± 0.004 to 0.02 ± 0.01 pg/min/g) and UV (0.4 ± 0.6 to 1.1 ± 0.3 µmol/min/g) responses to salt loading were markedly attenuated. These findings demonstrate that TNF-α contributes to saline-induced natriuresis, suggesting a physiological role for this cytokine in regulating renal excretory function during acute salt loading. These findings demonstrate for the first time that enhanced rate infusion of saline resulted in TNF-α production that exerts a natriuretic response, which strongly suggests a "physiological" role for this well-known proinflammatory cytokine in regulating renal function during acute salt loading. These results may confer therapeutic implications with predominant use of saline in patients with inflammatory conditions that are associated with significantly greater morbidity and mortality than those with predominant use of other balanced fluids.
肿瘤坏死因子-α（TNF-α）通过激活其在肾脏中的1型受体发挥利钠作用。尽管慢性高盐（HS）摄入通过单核吞噬细胞的免疫激活产生这种细胞因子，但急性盐负荷是否产生这种细胞因子并能诱导随后的利钠作用尚未得到研究。在此，我们在对照小鼠（n = 7）和TNF-α灭活剂依那西普（ETN；实验日前3天每天一次腹腔注射0.5 mg/kg；n = 7）处理的小鼠中，首先在等容状态下（0.9% NaCl，3 μL/min，持续60分钟；基线期），然后在增强输注速率下（12 μL/min，持续90分钟；盐负荷期）静脉输注等渗盐水期间，测量了TNF-α的血浆水平变化和尿排泄率（UV）。使用酶联免疫吸附测定（ELISA）试剂盒（Bioscience，沃本，马萨诸塞州）测定样品中的TNF-α浓度。在基线期，血浆中未检测到TNF-α水平，但在盐负荷期，对照小鼠（3.7±1.3 pg/mL）和ETN处理的小鼠（3.3±1.2 pg/mL）中的TNF-α水平均升高。在对照小鼠中，基线UV最小（0.01±0.002 pg/min/g），但在盐负荷期增加至0.1±0.03 pg/min/g（P<0.05），同时尿钠排泄增加（UV；0.5±0.2至4.8±1.2 μmol/min/g；P<0.05）。在ETN处理的小鼠中，盐负荷引起的UV（0.01±0.004至0.02±0.01 pg/min/g）和UV（0.4±0.6至1.1±0.3 μmol/min/g）反应均明显减弱。这些发现表明TNF-α有助于盐水诱导的利钠作用，提示该细胞因子在急性盐负荷期间调节肾脏排泄功能中具有生理作用。这些发现首次证明，增强速率输注盐水导致TNF-α产生，进而发挥利钠反应，这强烈提示这种著名的促炎细胞因子在急性盐负荷期间调节肾功能中具有“生理”作用。这些结果可能具有治疗意义，因为在炎症性疾病患者中主要使用盐水，其发病率和死亡率明显高于主要使用其他平衡液的患者。
