Extracellular superoxide dismutase functions as a major repressor of hypoxia-induced erythropoietin gene expression.
Hypoxia and biological responses to hypoxia are commonly encountered in both normal and pathologic cellular processes. Here we report that extracellular superoxide dismutase (EC-SOD) plays a major role in regulating the magnitude of hypoxia-induced erythropoietin (Epo) gene expression, thus implicating superoxide as an intermediary signal transduction molecule critical to this process. We found that mice which have the EC-SOD gene inactivated show a marked more than 100-fold elevation in hypoxia-induced Epo gene expression, compared with wild-type controls, which was both dose and time dependent. These mice also showed a significant increase in serum Epo levels after 1 d hypoxia. Interestingly, despite elevated Epo levels, reciprocal changes in hematocrit and reticulocyte counts were not found, suggesting that this newly synthesized Epo lacks functional hematopoietic effects. When EC-SOD was overexpressed in Hep3B cells, we found a significant reduction in Epo gene induction by both CoCl2 (50 microM) and hypoxia (1% O2). Similar findings were noted with another hypoxia-inducible gene, carbonic anhydrase IX. We conclude that EC-SOD functions as a major repressor of hypoxia-induced Epo gene expression, which implicates superoxide as a signaling intermediate whose downstream effects, at least in part, may be mediated by HIF-1alpha.
Zelko
Igor N
IN
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Folz
Rodney J
RJ
D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004920:Erythropoiesis; D004921:Erythropoietin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D007668:Kidney / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D013482:Superoxide Dismutase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D004921:Erythropoietin; D004247:DNA; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase