Excessive salt intake increases peritoneal solute transport rate via local tonicity-responsive enhancer binding protein in subtotal nephrectomized mice
Excessive salt intake increases peritoneal solute transport rate via local tonicity-responsive enhancer binding protein in subtotal nephrectomized mice
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DOI：
10.1093/ndt/gfz045
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发表时间：
2019-12-01
影响因子：
6.1
通讯作者：
Ito, Yasuhiko
中科院分区：
文献类型：
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作者：
Sun, Ting;Sakata, Fumiko;Ito, Yasuhiko
背景高腹膜转运与腹膜透析（PD）的高死亡率和技术失败相关。PD开始后6个月内通过腹膜平衡试验（PET）测量的基线腹膜溶质转运率（PSTR）在患者之间存在差异。据报告，钠储存在透析患者的皮肤或肌肉中。本研究探讨了尿毒症小鼠在不暴露于PD液的情况下过量摄入盐是否会引起腹膜改变。假手术（Sham）和肾大部切除（Nx）小鼠随机给予自来水或含1%氯化钠（NaCl）的水8周。然后进行PET以评估腹膜功能。以人间皮瘤细胞系Met-5A为研究对象。我们观察到，与饮用自来水（Nx+水）相比，饮用含1%NaCl饮用水（Nx+盐）的Nx小鼠PSTR更高，沿着腹膜中血管生成和炎症增强。阻断白细胞介素（IL）-6信号转导拯救了Nx+盐小鼠的腹膜转运功能。在培养的Met-5A中，培养基中的额外NaCl上调IL-6以及血管内皮生长因子-A，与张力响应增强子结合蛋白（TonEBP）的表达增加和核转位相关。TonEBP的敲低降低了由高张力引起的诱导。Nx+盐小鼠腹膜TonEBP表达较高，而去除高盐饮食降低了TonEBP水平，改善了腹膜转运功能。尿毒症状态下，过量的食盐摄入可引起腹膜功能和结构的改变。TonEBP调节高渗相关的炎症变化，并可能在高基线腹膜转运中发挥关键作用。
Background. High peritoneal transport is associated with high mortality and technical failure in peritoneal dialysis (PD). Baseline peritoneal solute transport rate (PSTR) as measured by the peritoneal equilibration test (PET) within 6 months after PD initiation varies between patients. Sodium is reported to be stored in the skin or muscle of dialysis patients. This study investigated whether excessive salt intake in uremic mice caused peritoneal alterations without exposure to PD fluid.Methods. Sham-operated (Sham) and subtotal nephrectomized (Nx) mice were randomly given tap water or 1% sodium chloride (NaCl)-containing water for 8 weeks. PET was then performed to evaluate peritoneal function. Human mesothelial cell line Met-5A was used for in vitro studies.Results. We observed higher PSTR in Nx mice with 1% NaCl-containing drinking water (Nx+salt) compared with those with tap water (Nx+water), along with enhanced angiogenesis and inflammation in the peritoneum. Blockade of interleukin (IL)-6 signaling rescued peritoneal transport function in Nx+salt mice. In cultured Met-5A, additional NaCl in the medium upregulated IL-6 as well as vascular endothelial growth factor-A, associated with increased expression and nuclear translocation of tonicity-responsive enhancer binding protein (TonEBP). Knockdown of TonEBP lowered the induction caused by high tonicity. Peritoneal TonEBP expression was higher in Nx+salt mice, while removal of high-salt diet lowered TonEBP level and improved peritoneal transport function.Conclusions. Excessive dietary salt intake caused peritoneal membrane functional and structural changes under uremic status. TonEBP regulated hypertonicity-related inflammatory changes and might play a crucial role in high baseline peritoneal transport.