Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project

Abstract

Iron is tightly connected to oxygen homeostasis and erythropoiesis. Our aim was to better understand how hypoxia regulates iron acquisition for erythropoiesis in humans, a topic relevant to common hypoxia-related disorders. Fortyseven healthy volunteers participated in the HIGHCARE project. Blood samples were collected at sea level and after acute and chronic exposure to high altitude (3400-5400 m above sea level). We investigated the modifications in hematocrit, serum iron indices, erythropoietin, markers of erythropoietic activity, interleukin-6, and serum hepcidin. Hepcidin decreased within 40 hours after acute hypoxia exposure (P < .05) at 3400 m, reaching the lowest level at 5400 m (80% reduction). Erythropoietin significantly increased (P < .001) within 16 hours after hypoxia exposure followed by a marked erythropoietic response supported by the increased iron supply. Growth differentiation factor-15 progressively increased during the study period. Serum ferritin showed a very rapid decrease, suggesting the existence of hypoxia-dependent mechanism(s) regulating storage iron mobilization. The strong correlation between serum ferritin and hepcidin at each point during the study indicates that iron itself or the kinetics of iron use in response to hypoxia may signal hepcidin down-regulation. The combined and significant changes in other variables probably contribute to the suppression of hepcidin in this setting. (Blood. 2011; 117(10):2953-2959) IntroductionIron is an essential element required as a cofactor for proteins managing oxygen transport, such as hemoglobin, myoglobin, and cytochromes. Hypoxia, which occurs in a broad range of pathologic or environmental conditions, is primarily sensed in vertebrates by the hypoxia inducible family of transcription factors (hypoxia inducible factors), which activate or repress genes involved in adaptations to low oxygen pressure. 1 In the erythropoietic compartment, which contains approximately 70% of the body iron, hypoxia stimulates erythropoiesis and promotes hemoglobin synthesis, which largely depends on iron availability. [2][3][4][5][6] Accordingly, both hypoxia and anemia induce the synthesis of erythropoietin (EPO) and are the 2 main signals that increase iron absorption independently of iron stores. [6][7][8][9] Thus, iron metabolism is tightly connected to oxygen homeostasis and erythropoiesis.The liver peptide hepcidin, codified by HAMP, is the key regulator of iron homeostasis. It acts by inhibiting intestinal iron absorption and release by macrophages, and its production is regulated by different stimuli, including inflammatory cytokines, 10 iron, 11 erythropoietic activity, 12-14 anemia, and hypoxia, 15-17 mainly at the transcriptional level as described in recent reviews. 18,19 Anemia could mediate hepcidin suppression through multiple mechanisms, including increased EPO or erythropoietic activity, increased iron demand, or liver hypoxia. 3 The nature of the erythropoietic regulator of hepcidin is still uncharacterized but may include one or more prote...

Four-Week Studies of Oral Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia

“…The effects of GSK1278863 on hemoglobin in both studies occurred with relatively small increases in plasma EPO concentrations, compared with changes in EPO concentration observed after administering injectable rhEPO. Measured plasma EPO concentrations in these studies remained within the range previously reported for patients with ESRD (range, 4.4-101.8 U/L) who were not treated with rhEPO 36 and were of similar magnitude to endogenous EPO concentrations seen during exposure to high altitudes, 37 whereas rhEPO concentrations were at least 12-fold higher in the rhEPO control group in the HDD study than in any of the GSK1278863 groups across both studies. Thus, GSK1278863 can increase (nondialysis patients not taking rhEPO) or maintain (HDD patients switched from rhEPO) hemoglobin while maintaining physiologic EPO concentrations.…”

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

“…In vivo, hypoxia has been shown to decrease hepcidin expression in both acute and chronic experimental models 21,38,39 as well as in humans. 40 Hypoxia is also known to induce the expression of renal erythropoietin, thereby promoting increased erythropoiesis to compensate for the decrease in ambient oxygen. The delayed hepcidin decrease in response to hypoxia in vivo could, therefore, be explained by the time needed to mount an increase in erythropoietic activity.…”

Roxadustat (FG-4592)

“…An important component is a reduction in hepcidin levels analogous to that seen during hypoxia at high altitude. 11 Roxadustat (also known as FG-4592) is an oral HIF-PH inhibitor (HIF-PHI). By inhibiting HIF-PHs and mimicking the response to a cellular reduction in oxygen levels, roxadustat increases HIF activity and promotes erythropoiesis.…”