Epo protects SOD2-deficient mouse astrocytes from damage by oxidative stress.
Erythropoietin (Epo) expression, which regulates erythropoiesis, has been shown in rat and mouse brain after hypoxia. A previous study from our laboratory showed that astrocytes from manganese-superoxide dismutase (SOD2) homozygous knockout (SOD2(-/-)) mice can survive under 5% O(2), but not under normal aerobic conditions. However, the mechanism involved is not clear. Our preliminary study using reverse transcriptase-polymerase chain reaction showed increased Epo mRNA expression in astrocytes cultured with 5% hypoxia compared with astrocytes under normal conditions. After administration of anti-sense Epo, protection decreased with time. Dose-dependent administration of Epo to SOD2(-/-) mouse astrocytes improved their survivability under normal conditions. Survivability of heterozygous SOD2(-/+) mutant and wild-type mouse astrocyte cultures was the same under normal conditions but, after administration of 2 mM of paraquat, a reactive oxygen species generator, survivability of the SOD2(-/+) astrocytes decreased remarkably compared with the wild-type cells. Epo administration 24 h before exposure to paraquat significantly improved the survivability of the SOD2(-/+) astrocytes. Western blot studies suggest that Jak-Stat signal transduction pathways are involved in this process. Our study demonstrates an important role for Epo in the protection of astrocytes from reactive oxygen species. We suggest that Epo can compensate in part for the antioxidant properties of mitochondrial SOD2 deficiency.
Liu
Jing
J
Department of Neurosurgery, Program in Neurosciences, Stanford University School of Medicine, California, USA.
Narasimhan
Purnima
P
Song
Yun Seon
YS
Nishi
Tatsuro
T
Yu
Fengshan
F
Lee
Yong-Sun
YS
Chan
Pak H
PH
D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D004921:Erythropoietin / Q000235:genetics / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D053614:Janus Kinase 2; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D012313:RNA / Q000096:biosynthesis; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000502:physiology; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics*; D013481:Superoxides / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D004921:Erythropoietin; D005609:Free Radicals; D053614:Janus Kinase 2; D016376:Oligonucleotides, Antisense; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D012313:RNA; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat