title: Protective effects of erythropoietin on astrocytic swelling after oxygen-glucose deprivation and reoxygenation: mediation through AQP4 expression and MAPK pathway.
abstract: Recent in vivo studies have shown that erythropoietin (EPO) offers strong protection against brain edema. However, the intracellular and molecular mechanisms behind this beneficial effect have not been specified. The aim of this study was to determine whether human erythropoietin (rhEPO) reduces the astrocytic swelling created by oxygen-glucose deprivation followed by reoxygenation (OGD/Reox) in vitro and whether this effect can be mediated through the modulation of aquaporin4 (AQP4) expression in the plasma membrane (PM) and phosphorylation of the mitogen-activated protein kinase pathway (MAPK) pathway. Our results showed that OGD/Reox produced increase in cell volume, morphological swelling, and mitochondrial swelling. These changes were associated with the up-regulation of AQP4 in PM and the over-activation of MAPK. Silencing AQP4 expression using small interfering ribonucleic acid for AQP4 was found to block astrocytic swelling. Inhibition of the over-activation of MAPK mitigated the PM AQP4 overabundance and cellular swelling. As expected, treatment with rhEPO significantly reduced the OGD/Reox-induced increase in cell volume, morphological swelling, and mitochondrial swelling as well as the up-regulation of AQP4 in PM. In addition, cultures treated with the neutralizing anti-EPO antibody worsened the PM AQP4 abundance and cellular swelling, abolishing the protective effects mediated by rhEPO treatment. Furthermore, the over-activation of these MAPK after OGD/Reox was attenuated by rhEPO treatment significantly. In conclusion, our data strongly suggest that rhEPO can protect astrocytes from swelling caused by ischemia and reperfusion-like injury. This neuroprotective capacity is partially mediated by diminishing the MAPK-activity-dependent overabundance of AQP4 in PM.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Chongqing 400016, China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Tang
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Huo
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Xie
authors.forename: Quanhong
authors.initials: Q
authors.lastname: Shi
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.forename: Xiaoshu
authors.initials: X
authors.lastname: Wang
authors.forename: Zhengbu
authors.initials: Z
authors.lastname: Liao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051401:Aquaporin 4 / Q000096:biosynthesis / Q000235:genetics*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004921:Erythropoietin / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; C554270:EPO protein, human; D011994:Recombinant Proteins; D004921:Erythropoietin; D005947:Glucose; D010100:Oxygen