Hypoxic regulation of erythropoiesis and iron metabolism

Abstract

Haase VH. Hypoxic regulation of erythropoiesis and iron metabolism. Am J Physiol Renal Physiol 299: F1-F13, 2010. First published May 5, 2010 doi:10.1152/ajprenal.00174.2010.-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.erythropoietin; hypoxia; hypoxia-inducible factors; iron; red blood cells ONE OF THE MOST EXTENSIVELY studied systemic adaptations to hypoxia is the stimulation of red blood cell (RBC) production. Over 100 years ago, Paul Bert and Denis Jourdanet observed the association between reduced atmospheric oxygen pressure and elevated RBC numbers in the blood of animals and humans (12, 13, 64). Francois-Gilbert Viault then demonstrated that ascent to a high altitude provided an acute and direct physiological stimulus for RBC production during his 1890 expedition to the Peruvian Andes by measuring the RBC increases in his own and the blood of his companions (156). It was the interest in understanding the physiological and molecular basis of this erythropoietic response that led to the discovery of erythropoietin (EPO) and that paved the way for the identification of the molecular machinery that senses oxygen and controls a wide spectrum of tissue-specific and systemic responses to hypoxia.The hypoxic induction of EPO serves as a paradigm of oxygen-dependent gene regulation, and the search for the transcription factor that mediates this induction led to the discovery of the hypoxia-inducible factor (HIF) as a key mediator of cellular adaptation to low oxygen. Recent experimental evidence suggests that HIF promotes erythropoiesis through coordinated cell type-specific hypoxia responses, which include increased EPO production in the kidney and liver, enhanced iron uptake and utilization, as well as changes in the bone marrow microenvironment that facilitate erythroid progenitor maturation and proliferation. Because of its central role in the hypoxic regulation of erythropoiesis, pharmacological targeting of the HIF oxygen-sensing pathway has the potential to become an effective, novel therapy in the treatment of anemia that is associated with inadequate EPO production.This review provides an overview of recent insights into the molecular mechanisms that underlie oxygen-dependent regulation of EPO synthesis, iron metabolism, and erythroid progenitor maturation and discusses their relevance to clinical disorders. Oxygen-Dependent Regulation of EPO ...

Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis

“…Moreover, HIF-2 but not HIF-1 seems to play a major role in iron metabolism and erythropoiesis. 26 HIF-2 regulates erythropoietin and key iron-related genes in the liver 25 and we recently showed that HIF-2 but not HIF-1 regulates iron absorption in enterocytes. 11 In a model of constitutive HIF-2 activation in hepatocytes (Vhlh/Hif1a KO), we found hepcidin to be strongly repressed.…”

Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glycoform analysis

“…Adults seem to have retained a hepatic production capacity of up to 10% of total EPO during normal conditions. Patients with end-stage renal disease require life-long therapy with recombinant EPO (rhEPO), but currently, therapeutic approaches for enhancing endogenous non-renal production of EPO is of high interest, as discussed in recent reviews [5,6]. Pharmacological manipulation of the hypoxia-inducible transcription factor (HIF) has been shown to stimulate endogenous EPO production [7].…”

Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8

“…HIF is a heterodimeric complex composed of a constitutively expressed HIF β-subunit and an oxygensensitive HIF α-subunit (6), in which all three α-subunits known to date (HIF-1α, -2α, and -3α) are targeted for rapid proteasomal degradation by the von Hippel-Lindau tumor suppressor pVHL, which acts as the substrate recognition component of an E3 ubiquitin ligase complex (9).…”