Modulation of endoplasmic reticulum chaperone GRP78 by high glucose in hippocampus of streptozotocin-induced diabetic mice and C6 astrocytic cells

• STZ-type 1 diabetic mice showed astrocytic activation and GRP78 reduction in hippocampus.
• High glucose induced astrocytic activation in C6 cells.
• High glucose reduced GRP78 expression, followed by reduced phosphorylation of Akt.
• High glucose induced ER stress and ROS production in C6 cells at early time point.
• Removal of ROS ameliorated GRP78 reduction in C6 cells.

Diabetes mellitus is known to increase the risk of neurodegeneration, and both diseases are reported to be linked to dysfunction of endoplasmic reticulum (ER). Astrocytes are important in the defense mechanism of central nervous system (CNS), with great ability of tolerating accumulation of toxic substances and sensitivity in Ca2+ homeostasis which are two key functions of ER. Here, we investigated the modulation of the glucose-regulated protein 78 (GRP78) in streptozotocin (STZ)-induced diabetic mice and C6 cells cultured in high glucose condition. Our results showed that more reactive astrocytes were presented in the hippocampus of STZ-induced diabetic mice. Simultaneously, decrease of GRP78 expression was found in the astrocytes of diabetic mice hippocampus.In in vitro study, C6 cells were treated with high glucose to investigate the role of high glucose in GRP78 modulation in astrocytic cells. GRP78 as well as other chaperones like GRP94, calreticulin and calnexin, transcription levels were down-regulated after high glucose treatment. Also C6 cells challenged with 48 h high glucose were activated, as indicated by increased level of glial fibrillary acidic protein (GFAP). Activated C6 cells simultaneously exhibited significant decrease of GRP78 level and was followed by reduced phosphorylation of Akt. Moreover, unfolded protein response was induced as an early event, which was marked by the induction of CHOP with high glucose treatment, followed by the reduction of GRP78 after 48 h. Finally, the upsurge of ROS production was found in high glucose treated C6 cells and chelation of ROS could partially restore the GRP78 expression. Taken together, these data provide evidences that high glucose induced astrocytic activation in both in vivo and in vitro diabetic models, in which modulation of GRP78 would be an important event in this activation.