This Article Full Text Full Text (PDF) All Versions of this Article: 146/1/332    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zelko, I. N. Articles by Folz, R. J. Search for Related Content PubMed PubMed Citation Articles by Zelko, I. N. Articles by Folz, R. J.

Extracellular Superoxide Dismutase Functions as a Major Repressor of Hypoxia-Induced Erythropoietin Gene Expression

Departments of Medicine (I.N.Z., R.J.F.) and Cell Biology (R.J.F.), Duke University Medical Center, Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Rodney J. Folz, M.D., Ph.D., Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Duke University Medical Center, Box 2620/Room 331 MSRB, Durham, North Carolina 27710. E-mail: rodney.folz{at}duke.edu.

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 µM) 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-1.

This article has been cited by other articles:

				K. E. Jie, M. C. Verhaar, M.-J. M. Cramer, K. van der Putten, C. A. J. M. Gaillard, P. A. Doevendans, H. A. Koomans, J. A. Joles, and B. Braam Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors Am J Physiol Renal Physiol, November 1, 2006; 291(5): F932 - F944. [Abstract] [Full Text] [PDF]

				J. K. Maranchie and Y. Zhan Nox4 Is Critical for Hypoxia-Inducible Factor 2-{alpha} Transcriptional Activity in von Hippel-Lindau-Deficient Renal Cell Carcinoma Cancer Res., October 15, 2005; 65(20): 9190 - 9193. [Abstract] [Full Text] [PDF]

				J. W. Park, W.-N. Qi, Y. Cai, I. Zelko, J. Q. Liu, L.-E. Chen, J. R. Urbaniak, and R. J. Folz Skeletal muscle reperfusion injury is enhanced in extracellular superoxide dismutase knockout mouse Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H181 - H187. [Abstract] [Full Text] [PDF]