School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, 210094, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Molecules. 2019 Dec 19;25(1):25. doi: 10.3390/molecules25010025.
Angiotensin II (Ang II) participates in the pathogenesis of liver injury. Our previous publications reported that myeloid differentiation protein 2 (MD2) mediates Ang II-induced cardiac and kidney inflammation by directly binding to Ang II. Thus, we hypothesize that MD2 is critical to Ang II-induced liver injury. Subcutaneous injections of Ang II for 8 weeks were adopted to build the liver injury model. With a specific MD2 inhibitor L6H21 and MD2 knockout mice, we reported that MD2 inhibition and knockout significantly mitigate liver inflammation and fibrosis in mice injected with Ang II. To be more specific, the functional and pathological damages induced by Ang II were mitigated by L6H21 or MD2 knockout. MD2 knockout or L6H21 administration inhibited the Ang II-induced upregulation of fibrosis markers, inflammatory cytokines, and adhesion molecules in gene or protein levels. The activation of NF-κB and Extracellular signal-regulated kinases (ERK) induced by Ang II was also reversed by L6H21 treatment or MD2 deficiency. Note that the co-immunoprecipitation study showed that L6H21 downregulated the ANG II-induced toll-like receptor 4 (TLR4)/MD2 complex in liver tissues while having no effects on MD2 expression. Our results reported the critical role of MD2 in the progress of liver injury and suggested that MD2 is a potential therapeutic target for liver injury.
血管紧张素 II（Ang II）参与肝损伤的发病机制。我们之前的研究报告表明，髓样分化蛋白 2（MD2）通过直接与 Ang II 结合，介导 Ang II 诱导的心脏和肾脏炎症。因此，我们假设 MD2 对 Ang II 诱导的肝损伤至关重要。我们采用皮下注射 Ang II 8 周的方法构建肝损伤模型。通过使用特异性 MD2 抑制剂 L6H21 和 MD2 敲除小鼠，我们报道了 MD2 抑制和敲除可显著减轻 Ang II 注射小鼠的肝炎症和纤维化。更具体地说，Ang II 诱导的功能和病理损伤被 L6H21 或 MD2 敲除所减轻。MD2 敲除或 L6H21 给药抑制了 Ang II 诱导的纤维化标志物、炎症细胞因子和黏附分子在基因或蛋白水平的上调。Ang II 诱导的 NF-κB 和细胞外信号调节激酶（ERK）的激活也被 L6H21 处理或 MD2 缺乏所逆转。值得注意的是，共免疫沉淀研究表明，L6H21 下调了 Ang II 诱导的肝组织中 Toll 样受体 4（TLR4）/MD2 复合物，而对 MD2 表达没有影响。我们的研究结果表明 MD2 在肝损伤进展中的关键作用，并提示 MD2 是肝损伤的潜在治疗靶点。
