Epo protects SOD2‐deficient mouse astrocytes from damage by oxidative stress

Abstract

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.