Sodium chloride promotes tissue inflammation via osmotic stimuli in subtotal-nephrectomized mice
Sodium chloride promotes tissue inflammation via osmotic stimuli in subtotal-nephrectomized mice
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DOI：
10.1038/labinvest.2017.4
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发表时间：
2017-02
影响因子：
5
通讯作者：
F. Sakata;Yasuhiko Ito;M. Mizuno;Akiho Sawai;Yasuhiro Suzuki;T. Tomita;Mitsuhiro Tawada;A. Tanaka;A. Hirayama;A. Sagara;T. Wada;S. Maruyama;T. Soga;S. Matsuo;E. Imai;Y. Takei
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作者：
F. Sakata;Yasuhiko Ito;M. Mizuno;Akiho Sawai;Yasuhiro Suzuki;T. Tomita;Mitsuhiro Tawada;A. Tanaka;A. Hirayama;A. Sagara;T. Wada;S. Maruyama;T. Soga;S. Matsuo;E. Imai;Y. Takei
慢性炎症通常与高全因和心血管死亡率相关，在肾衰竭患者中普遍存在;然而，确切的机制仍不清楚。据报道，高盐摄入通过渗透刺激引起钠或氯的积累而诱导淋巴管生成和自身免疫性疾病。此外，最近有报道称，钠储存在透析患者的四肢中。我们研究了高盐负荷对肾大部切除小鼠（5/6 Nx）和培养细胞的组织和全身炎症的影响和机制。5/6 Nx/NaCl组腹腔壁（P< 0.001）、心脏（P< 0.05）和主动脉旁组织（P< 0.001）中的巨噬细胞浸润显著高于5/6 Nx/Water组，但两组间血压和肾功能无显著差异。与5/6 Nx/Water相比，5/6 Nx/NaCl组腹膜壁和心脏组织中的白细胞介素-6、单核细胞趋化蛋白-1（MCP-1）、血清和糖皮质激素诱导的激酶1（Sgk 1）和张力反应增强子结合蛋白（TonEBP）mRNA显著升高。钠储存在腹壁中，施加高渗透条件。在5/6 Nx/NaCl中，盐负荷的抑制减少了与TonEBP降低相关的巨噬细胞浸润。与5/6 Nx/NaCl/Wild小鼠相比，5/6 Nx/NaCl/CC趋化因子受体2（CCR 2，MCP-1受体）缺陷小鼠中与盐负荷诱导的纤维化相关的巨噬细胞浸润减少，表明CCR 2是5/6 Nx + NaCl负荷中巨噬细胞浸润所需的。在培养的间皮细胞和心肌细胞中，高浓度NaCl培养基诱导MCP-1、Sgk 1和TonEBP mRNA的表达，所有这些都被TonEBP siRNA抑制，表明MCP-1和Sgk 1都是TonEBP的下游。我们的研究表明，高NaCl摄入诱导MCP-1表达，导致巨噬细胞浸润通过TonEBP-MCP-1途径在5/6 Nx/NaCl小鼠，TonEBP在高盐肾功能衰竭患者的炎症中起核心作用。
Chronic inflammation, which is often associated with high all-cause and cardiovascular mortality, is prevalent in patients with renal failure; however, the precise mechanisms remain unclear. High-salt intake was reported to induce lymphangiogenesis and autoimmune diseases via osmotic stimuli with accumulation of sodium or chloride. In addition, sodium was recently reported to be stored in the extremities of dialysis patients. We studied the effects and mechanisms of high salt loading on tissue and systemic inflammation in subtotal-nephrectomized mice (5/6Nx) and in cultured cells. Macrophage infiltration in the peritoneal wall (P< 0.001), heart (P< 0.05) and para-aortic tissues (P< 0.001) was significantly higher in 5/6Nx with salt loading (5/6Nx/NaCl) than in 5/6Nx without salt loading (5/6Nx/Water); however, there were no significant differences in blood pressure and renal function between the groups. Tissue interleukin-6, monocyte chemotactic protein-1 (MCP-1), serum-and glucocorticoid-inducible kinase 1 (Sgk1) and tonicity-responsive enhancer binding protein (TonEBP) mRNA were significantly elevated in the peritoneal wall and heart with 5/6Nx/NaCl when compared with 5/6Nx/Water. Sodium was stored in the abdominal wall, exerting high-osmotic conditions. Reversal of salt loading reduced macrophage infiltration associated with decreased TonEBP in 5/6Nx/NaCl. Macrophage infiltration associated with fibrosis induced by salt loading was decreased in the 5/6Nx/NaCl/CC chemokine receptor 2 (CCR2, receptor of MCP-1)-deficient mice when compared with 5/6Nx/NaCl/Wild mice, suggesting that CCR2 is required for macrophage infiltration in 5/6Nx with NaCl loading. In cultured mesothelial cells and cardiomyocytes, culture media with high NaCl concentration induced MCP-1, Sgk1 and TonEBP mRNA, all of which were suppressed by TonEBP siRNA, indicating that both MCP-1 and Sgk1 are downstream of TonEBP. Our study indicates that high NaCl intake induces MCP-1 expression leading to macrophage infiltration via the TonEBP-MCP-1 pathway in 5/6Nx/NaCl mice, and that TonEBP has a central role in inflammation in patients with renal failure taking high salt.