Research Papers:

Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy

Zhouguang Wang _, Yan Huang, Yi Cheng, Yi Tan, Fenzan Wu, Jiamin Wu, Hongxue Shi, Hongyu Zhang, Xichong Yu, Hongchang Gao, Li Lin, Jun Cai, Jinsan Zhang, Xiaokun Li, Lu Cai and Jian Xiao

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Oncotarget. 2016; 7:78455-78472. https://doi.org/10.18632/oncotarget.12925

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Zhouguang Wang1, Yan Huang1, Yi Cheng1, Yi Tan1,2, Fenzan Wu1, Jiamin Wu1, Hongxue Shi1, Hongyu Zhang1, Xichong Yu1, Hongchang Gao1, Li Lin1, Jun Cai2, Jinsan Zhang1, Xiaokun Li1,2, Lu Cai1,2 and Jian Xiao1

1 Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China

2 Department of Pediatrics, Children’s Hospital Research Institute, the University of Louisville, Louisville, Kentucky, USA

Correspondence to:

Jian Xiao, email:

Lu Cai, email:

Keywords: ER stress, inflammation, apoptosis, p-JNK, diabetes

Received: June 09, 2016 Accepted: October 19, 2016 Published: October 26, 2016


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.

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