Hypoxic regulation of erythropoiesis and iron metabolism

Department of Medicine, Vanderbilt School of Medicine, Nashville, Tennessee 37232, USA.
AJP Renal Physiology (Impact Factor: 3.25). 07/2010; 299(1):F1-13. DOI: 10.1152/ajprenal.00174.2010
Source: PubMed


The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of erythropoietin (EPO), which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.

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    • "Recently, it was shown that NF-κB (nuclear factor κB) is a modulator of HIF 2 expression in the presence of normal oxygen pressure (Haase et al., 2010, Willam, 2014). NF-κB indirectly controls HIF 2α through its control of HIF 1β (van Uden et al., 2011). "

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    • "However, this could not be confirmed in the isolated hepatocytes [93], and other indirect pathways by which HIF regulates hepcidin expression may exist. It has been found that HIF could regulate renal and hepatic EPO synthesis directly under hypoxia [94], and the activation of hepatic HIF itself without the concomitant increase in EPO transcription did not suppress hepcidin expression [95]. Therefore, the regulation of HIF on hepcidin may be mediated by affecting the EPO synthesis. "
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    • "Upon stabilization, alpha subunits enter the nucleus, where they dimerize with HIF-β. The dimer binds to a specific base sequence in the promoter region of genes called hypoxia response element, HRE, to induce the expression of genes (for recent reviews see (Semenza, 2009; Haase, 2010)). Besides stabilization, HIF-alpha subunits are also controlled at the transcriptional level (Görlach, 2009; Semenza, 2009). "
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