Extracellular superoxide dismutase functions as a major repressor of hypoxia-induced erythropoietin gene expression

Endocrinology. 2005 Jan;146(1):332-40. doi: 10.1210/en.2004-1007. Epub 2004 Sep 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • DNA / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Erythropoiesis
  • Erythropoietin / antagonists & inhibitors*
  • Erythropoietin / genetics
  • Erythropoietin / metabolism
  • Gene Expression
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Hypoxia / physiopathology
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • Kidney / enzymology
  • Mice
  • Mice, Knockout
  • RNA, Messenger / antagonists & inhibitors
  • Superoxide Dismutase / metabolism*
  • Transcription Factors / metabolism


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Transcription Factors
  • Erythropoietin
  • DNA
  • Sod3 protein, mouse
  • Superoxide Dismutase