Regulation of erythropoiesis by hypoxia-inducible factors.

Publication Type:

Journal Article

Source:

Blood reviews, Volume 27, Issue 1, p.41-53 (2013)

Keywords:

Anoxiadigestive disease, digestive deseases Basic Helix-Loop-Helix Transcription Factorsdigestive disease, digestive deseases Bone Marrow Cellsdigestive disease, digestive deseases Cell Differentiationdigestive disease, digestive deseases Cell Proliferationdigestive disease, digestive deseases Erythrocytesdigestive disease, digestive deseases Erythropoiesisdigestive disease, digestive deseases Erythropoietindigestive disease, digestive deseases Gene Expression Regulationdigestive disease, digestive deseases Humansdigestive disease, digestive deseases Hypoxia-Inducible Factor 1digestive disease, digestive deseases Irondigestive disease, digestive deseases Kidneydigestive disease, digestive deseases Liverdigestive disease, digestive deseases Oxygendigestive disease, digestive deseases Signal Transduction

Abstract:

A classic physiologic response to systemic hypoxia is the increase in red blood cell production. Hypoxia-inducible factors (HIFs) orchestrate this response by inducing cell-type specific gene expression changes that result in increased erythropoietin (EPO) production in kidney and liver, in enhanced iron uptake and utilization and in adjustments of the bone marrow microenvironment that facilitate erythroid progenitor maturation and proliferation. In particular HIF-2 has emerged as the transcription factor that regulates EPO synthesis in the kidney and liver and plays a critical role in the regulation of intestinal iron uptake. Its key function in the hypoxic regulation of erythropoiesis is underscored by genetic studies in human populations that live at high-altitude and by mutational analysis of patients with familial erythrocytosis. This review provides a perspective on recent insights into HIF-controlled erythropoiesis and iron metabolism, and examines cell types that have EPO-producing capability. Furthermore, the review summarizes clinical syndromes associated with mutations in the O(2)-sensing pathway and the genetic changes that occur in high altitude natives. The therapeutic potential of pharmacologic HIF activation for the treatment of anemia is discussed.