Modulation of endoplasmic reticulum chaperone GRP78 by high glucose in hippocampus of streptozotocin-induced diabetic mice and C6 astrocytic 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 Ca(2+) 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 48h 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 48h. 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.
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong.
Daniella P K
DP
Wong
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong; Department of Biology, Hong Kong Baptist University, Hong Kong.
John M T
JM
Chu
Department of Anaestheiology, The University of Hong Kong, Hong Kong.
Victor K L
VK
Hung
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong.
Dicky K M
DK
Lee
School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong.
Christopher H K
CH
Cheng
Department of Biology, Hong Kong Baptist University, Hong Kong.
Ken K L
KK
Yung
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong. Electronic address: kkmyue@hkbu.edu.hk.
Kevin K M
KK
Yue
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000523:psychology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; D005904:Glial Fibrillary Acidic Protein; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt
ATF6; Astrocytes; CAT; CNS; DM; Diabetes; ER; Endoplasmic reticulum; GFAP; GPx-1; GRP; GRP78; H(2)O(2); HG; HO-1; Heme oxygenase 1; High glucose; IRE1; N-acetylcysteine; NAC; NG; Normal glucose; OC; Osmotic control; PERK; PKR-like ER kinase; ROS; SOD; STZ; STZ type 1 diabetic mice; UPR; activating transcription factor 6; catalase; central nervous system; diabetes mellitus; glial fibrillary acidic protein; glucose-regulated protein; glutathione peroxidase 1; hydrogen peroxide; inositol-requiring enzyme 1; reactive oxygen species; streptozotocin; superoxide dismutases; unfolded protein response