title: The dynamic changes of endoplasmic reticulum stress pathway markers GRP78 and CHOP in the hippocampus of diabetic mice.
abstract: Diabetic encephalopathy has recently been recognized late complication of diabetes resulting in progressive cognitive deficits. Emerging evidence has indicated that endoplasmic reticulum (ER) stress-mediated apoptosis is involved in the pathogenesis of diabetic eye and kidney as well as non-diabetic neurodegeneration. However, there was little direct evidence for the involvement of ER stress in diabetic encephalopathy up to now. In the present work, we investigated the role of ER stress in the pathogenesis of diabetic encephalopathy. Our results have demonstrated the existence of ER stress in the hippocampus of streptozotocin (STZ)-induced diabetic mice. STZ injection i.p. rapidly induced up-regulation of the ER stress marker, the prosurvival chaperone glucose-regulated protein 78 (GRP78), as early as 6-24h and persisted at least for up to 72h in the hippocampus of mice, indicating the UPR activation soon after STZ administration. The increased expression of GRP78 in hippocampal cells is to relieve the ER stress. With the development of diabetes, the expression of GRP78 decreases while the expression of UPR-associated proapoptotic transcriptional regulator C/EBP homologous protein (CHOP) increases significantly in the hippocampal neurons of diabetic mice from 1 week after STZ administration to 12 weeks/the end of the study. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells in the hippocampus of diabetic mice were largely colocalized with NeuN- and CHOP-positive cells, indicating that the up-regulation of CHOP in hippocampal neurons of diabetic mice may promote neuronal apoptosis and account for the damaged learning and memory ability of diabetic mice. Therefore, our study provides evidence that ER stress may play an important role in the pathogenesis of neuronal degeneration and may contribute to cognitive dysfunction of diabetic encephalopathy.
authors.affiliation: Central Laboratory, Xuanwu Hospital of Capital Medical University, Beijing 100053, PR China; Beijing Geriatric Medical Research Center, Beijing 100053, PR China; Key Laboratory of Neurodegenerative Diseases of Ministry of Education, Beijing 100053, PR China. Electronic address: yongmeizhao@hotmail.com.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Central Laboratory, Xuanwu Hospital of Capital Medical University, Beijing 100053, PR China; Beijing Geriatric Medical Research Center, Beijing 100053, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Central Laboratory, Xuanwu Hospital of Capital Medical University, Beijing 100053, PR China; Beijing Geriatric Medical Research Center, Beijing 100053, PR China; Key Laboratory of Neurodegenerative Diseases of Ministry of Education, Beijing 100053, PR China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Central Laboratory, Xuanwu Hospital of Capital Medical University, Beijing 100053, PR China; Beijing Geriatric Medical Research Center, Beijing 100053, PR China.
authors.forename: Sen
authors.initials: S
authors.lastname: Li
authors.affiliation: Central Laboratory, Xuanwu Hospital of Capital Medical University, Beijing 100053, PR China; Key Laboratory of Neurodegenerative Diseases of Ministry of Education, Beijing 100053, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D017209:Apoptosis; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000523:psychology; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D051742:Transcription Factor CHOP
keywords: Apoptosis; CHOP; Diabetic encephalopathy; Endoplasmic reticulum stress; GRP78; Hippocampus