Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy.
Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy.
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内质网应激诱导的神经元炎症反应和细胞凋亡可能在糖尿病脑病的发展中发挥关键作用。
DOI：
10.18632/oncotarget.12925
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发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Xiao J
中科院分区：
文献类型：
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作者：
Wang Z;Huang Y;Cheng Y;Tan Y;Wu F;Wu J;Shi H;Zhang H;Yu X;Gao H;Lin L;Cai J;Zhang J;Li X;Cai L;Xiao J
我们认为糖尿病脑病（DEP）可能是由内质网（ER）介导的中枢神经系统炎症反应和细胞凋亡共同作用的结果。为了验证这一观点，我们研究了Sprague-Dawley大鼠高脂饮食/链脲佐菌素诱导的2型糖尿病模型中神经元内质网应激及相关炎症和细胞凋亡。糖尿病大鼠海马CA1区内质网应激标志物包括葡萄糖调节蛋白78（GRP78）、转录激活因子6（ATF-6）、X盒结合蛋白1（XBP-1）、C/EBP同源蛋白和磷酸化Jun N末端激酶（p-JNK）的表达明显升高。这些变化还伴随着NF-κ B的激活以及炎症细胞因子、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平的升高。体外培养的海马神经元暴露于高糖（HG）后，通过内质网应激、JNK和NF-κ B活化以及炎症反应的增强，诱导了糖尿病样效应。通过4-苯基丁酸酯（4-PBA）抑制ER应激或通过特异性抑制剂阻断JNK活性或转染DN-JNK可减轻HG诱导的炎症和相关凋亡。为了验证体外发现，体内应用4-PBA导致糖尿病诱导的神经元ER应激、炎症和细胞死亡的显著减少，从而预防DEP。这些结果表明，糖尿病诱导的神经元内质网应激在糖尿病诱导的神经元炎症和细胞死亡中起关键作用，导致DEP的发展。
We assumed that diabetic encephalopathy (DEP) may be induced by endoplasmic reticulum (ER)-mediated inflammation and apoptosis in central nervous system. To test this notion, here we investigated the neuronal ER stress and associated inflammation and apoptosis in a type 2 diabetes model induced with high-fat diet/streptozotocin in Sprague-Dawley rats. Elevated expressions of ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor-6 (ATF-6), X-box binding protein-1 (XBP-1), and C/EBP homologous protein, and phosphor-Jun N-terminal kinase (p-JNK) were evident in the hippocampus CA1 of diabetic rats. These changes were also accompanied with the activation of NF-κB and the increased levels of inflammatory cytokines, tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6). Mechanistic study with in vitro cultured hippocampus neurons exposed to high glucose (HG), which induced a diabetes-like effects, shown by increased ER stress, JNK and NF-κB activation, and inflammatory response. Inhibition of ER stress by 4-phenylbutyrate (4-PBA) or blockade of JNK activity by specific inhibitor or transfection of DN-JNK attenuated HG-induced inflammation and associated apoptosis. To validate the in vitro finding, in vivo application of 4-PBA resulted in a significant reduction of diabetes-induced neuronal ER stress, inflammation and cell death, leading to the prevention of DEP. These results suggest that diabetes-induced neuronal ER stress plays the critical role for diabetes-induced neuronal inflammation and cell death, leading to the development of DEP.