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Oxygen–Glucose Deprivation (OGD) Modulates the Unfolded Protein Response (UPR) and Inflicts Autophagy in a PC12 Hypoxia Cell Line Model

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Abstract

Hypoxia is the lack of sufficient oxygenation of tissue, imposing severe stress upon cells. It is a major feature of many pathological conditions such as stroke, traumatic brain injury, cerebral hemorrhage, perinatal asphyxia and can lead to cell death due to energy depletion and increased free radical generation. The present study investigates the effect of hypoxia on the unfolded protein response of the cell (UPR), utilizing a 16-h oxygen–glucose deprivation protocol (OGD) in a PC12 cell line model. Expression of glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94), key players of the UPR, was studied along with the expression of glucose-regulated protein 75 (GRP75), heat shock cognate 70 (HSC70), and glyceraldehyde 3-phosphate dehydrogenase, all with respect to the cell death mechanism(s). Cells subjected to OGD displayed upregulation of GRP78 and GRP94 and concurrent downregulation of GRP75. These findings were accompanied with minimal apoptotic cell death and induction of autophagy. The above observation warrants further investigation to elucidate whether autophagy acts as a pro-survival mechanism that upon severe and prolonged hypoxia acts as a concerted cell response leading to cell death. In our OGD model, hypoxia modulates UPR and induces autophagy.

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Abbreviations

CMA:

Chaperone-mediated autophagy

DMEM:

Dulbecco’s modified Eagle’s medium

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GRP75:

Glucose-regulated protein 75

GRP78:

Glucose-regulated protein 78

GRP94:

Glucose-regulated protein 94

HSC70:

Heat shock cognate 70

OGD:

Oxygen–glucose deprivation

PC12:

Rat pheochromocytoma cell line 12

PCR:

Polymerase chain reaction

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

UPR:

Unfolded protein response

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Acknowledgments

The authors thank Professor Zafiroula Iakovidou-Kritsi director of the laboratory of General Biology, Department of Biological Sciences and Preventive Medicine, Faculty of Medicine, Aristotle University of Thessaloniki, for granting access to fluorescent microscopy.

Funding

The present work was supported by the Program for Basic Research Activity Enhancement of the Research Committee of Aristotle University (Project Number 89337), European Union/European Social Fund EPEAEK PYTHGORAS II (Project Number 13) as well as the yearly Laboratory of Physiology fund allocation. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Laboratory of Physiology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Theofanis Vavilis, Nikoleta Delivanoglou, Eleni Aggelidou, Eleni Stamoula, Maria Albani & Aristeidis Kritis

  2. Laboratory of Physiology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Kyriakos Mellidis & Antigone Lazou

  3. Laboratory of Histology, Embryology and Anthropology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Aikaterini Kaidoglou

  4. Department of Pathology, General Hospital of Thessaloniki “G. Papanikolaou”, Thessaloniki, Greece

    Angeliki Cheva

  5. Laboratory of Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Chryssa Pourzitaki

  6. Unit of Human Reproduction, 1st Department of Obstetrics and Gynaecology, Aristotle University Medical School, Papageorgiou General Hospital, Thessaloniki, Greece

    Katerina Chatzimeletiou

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  1. Theofanis Vavilis
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Correspondence to Aristeidis Kritis.

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Vavilis, T., Delivanoglou, N., Aggelidou, E. et al. Oxygen–Glucose Deprivation (OGD) Modulates the Unfolded Protein Response (UPR) and Inflicts Autophagy in a PC12 Hypoxia Cell Line Model. Cell Mol Neurobiol 36, 701–712 (2016). https://doi.org/10.1007/s10571-015-0250-2

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