Hypoxic regulation of erythropoiesis and iron metabolism pdf

An overview of molecular basis of iron metabolism regulation. Hypoxia has profound effects on iron absorption and results in increased iron acquisition and erythropoiesis when humans move from sea level to altitude. This notion is supported by clinical observations in patients with. Iron is required for efficient oxygen transport, and hypoxia signaling links erythropoiesis with iron homeostasis. Adaptation of iron transport and metabolism to acute high. Hypoxia induced downregulation of hepcidin is mediated by. The dual specificity of irp1aconitase may have a functional role in the regulation of erythropoiesis by iron availability, as the provision of the aconitase product isocitrate reverses some of the suppressive effect of iron deprivation on erythropoiesis and the enzymatic inhibition of aconitase has the opposite effect bullock et al. Erythropoiesis mediated regulation of hepcidin is an area of increasing importance and recent studies have. Jci hypoxiainducible factor regulates hepcidin via. Wojtal,1 beat mullhaupt, 1,7,8 michael fried,1,8 max gassmann,3,8 thomas lutz,3,8 and. One component of this pathway, hypoxia inducible factor hif, is a transcription factor that is highly active in hypoxic cells. The absorption of iron by duodenal enterocytes is dependent on body iron stores, hypoxia, inflammation and rate of erythropoiesis.

Design using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600 m, for 6 h. Influence of postexercise hypoxic exposure on hepcidin. Disorders of erythropoiesis,erythrocytes and iron metabolism chapter2regulationoferythropoiesis 47 hsc cmp mep bfumk platelet primitive bfue megacaryocyte cfue red blood cell mature bfue proerythroblast reticulocyte erythroblast cd34 cd33 epor cd71 glycophorin a hladr ckit bfuep bfuem cfue proebl erythroblasts baso i baso ii. Schmidt,5 bruno galy,4 alisa damnernsawad,2 aimee t. Serum iron levels depend on intestinal absorption from the diet, transport capacity in the blood, recycling of iron released from phagocytosed erythrocytes, and the release of iron from other tissue stores, such as the liver. A paradigm of hypoxic gene regulation the human epo gene encodes a glycoprotein hormone, which consists of 165 amino acids in its circulating form. By coordinating iron availability and erythropoiesis by increasing epo, vhlhif supports production of properly formed mature erythrocytes, correcting anemia. Hypoxia induces a highly conserved signaling pathway in cells under conditions of low levels of o2. Hypoxia inducible factor hif2 regulates erythropoietin epo. Given the links among oxygen transport, erythropoiesis, and iron metabolism, there are potential associations between the physiol ogy of hypoxic response and. The current clinical experi ence with pharmacologic hif.

Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Here, we show that translational regulation of hypoxia inducible factor 2. Exquisite shortterm control of erythropoiesis is regulated by the kidneyderived cytokine erythropoietin epo, which is induced under hypoxic conditions and stimulates the terminal proliferation and differentiation of cfue progenitors. Iron is an essential but potentially hazardous biometal.

Hypoxia coordinates epo synthesis with iron metabolism. Regulation of cellular iron metabolism biochemical journal. Red blood cell production is a finely tuned process that requires coordinated oxygen and irondependent regulation of cell differentiation and iron metabolism. Thus iron supply to erythropoiesis is strictly dependent on the iron.

Normalization of iron and tissue oxygenation act to reduce hepatic hif1 levels as a feedback regulation on the system. This observation suggests that ironindependent systemic signals must play a major role in the physiologic regulation of hepcidin under hypoxic conditions. The role of hif2 in hypoxia induced erythropoiesis extends beyond the transcriptional control of epo. It binds ferroportin on enterocytes, macrophages and hepatocytes triggering its internalisation and lysosomal degradation. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. A critical regulator of iron metabolism during hypoxia. Therefore, hepcidin levels are tightly regulated by several factors, such as changes in body iron storage, inflammation, erythropoiesis and hypoxia. Role of the hypoxia inducible factors in iron metabolism. Anaemia is a clinical hallmark of advanced kidney disease, characterized by insufficient erythropoiesis due to inadequate erythropoietin production in the kidney, inflammation and iron deficiency. Therefore, it is not surprising that some key proteins involved in iron metabolism are oxygen regulated. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone.

Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. Hypoxic regulation of erythropoiesis and iron metabolism core. To further explore the regulation of iron metabolism. Regulation of iron homoeostasis hepcidin, synthesised by hepatocytes in response to iron concentrations, inflammation, hypoxia and erythropoiesis, is the main iron regulatory hormone. Mar 14, 2011 diagram of the feedback regulation of erythropoiesis lack of o 2 hypoxia is a stimulus for the synthesis of erythropoietin epo, primarily in the kidneys. Red blood cell production erythropoiesis is the single largest consumer of iron in the body.

Hepcidin, a small polypeptide produced by hepatocytes, plays a central role in regulating iron uptake by promoting internalization and degradation of ferroportin, the only known cellular iron exporter. However, some controversy exists as to whether hifs interact with hepatic hepcidin production in regulation of the iron metabolism. Role and regulation of iron metabolism in erythropoiesis and. Cells are able to regulate themselves the expression of the iron metabolism related genes through different posttranscriptional mechanisms, such as the alternative splicing, micrornas, the irpire system and the proteolytic cleavage. Hepcidin regulation is finely tuned according to circulating and stored iron through a hormonal homeostatic mechanism. Regulation of the hypoxic response in candida albicans. Hif2 induces renal and hepatic epo synthesis in response to hypoxia, which results in increased serum epo levels circle, stimulating erythropoiesis.

Iron demand in bone marrow increases when erythropoiesis is stimulated by hypoxia via increased erythropoietin epo synthesis in kidney and liver. Major advances have been made in understanding the regulation of hepcidin production, and consequently the availability of iron for erythropoiesis. A holistic approach of erythropoiesis and iron in anemia. Regulation of the iron homeostatic hormone hepcidin. Besides the systemic regulation of iron metabolism mediated by hepcidin, cellular regulatory processes also occur. Reciprocal regulation between hepcidin and erythropoiesis. Hypoxia inducible factor activators in renal anemia. This necessitates increased intestinal iron uptake, an augmentation of serum iron binding capacity and enhanced mobilization of iron from internal stores.

The results establish a pivotal role for hif1 in the regulation of yolk sac erythropoiesis and iron metabolism in mouse development. Pdf hypoxic regulation of erythropoiesis and iron metabolism. Iron metabolism is adjusted to match iron demand from increased erythropoiesis. The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Hypoxiainducible factors link iron homeostasis and.

Iron deficiency id progresses to iron deficiency anemia. Hypoxic regulation of erythropoiesis and iron metabolism ncbi. One component of this pathway, hypoxiainducible factor hif, is a transcription factor that is highly active in hypoxic cells. New insights into the links between hypoxia and iron homeostasis. Hif2 has a key role in adult erythropoiesis, by regulating the erythropoietin hormone epo but also by increasing iron mobilization via two essential mechanisms. Shown is the chemical structure of a hifphd inhibitor phi capable of effectively stimulating the production of endogenous epo in hemodialysis patients. Given the links among oxygen transport, erythropoiesis, and iron metabolism, there are potential associations between the physiology of hypoxic response and the control of iron availability. Nevertheless, disorders of iron metabolism are diverse and can be caused by insufficiency, overload or iron maldistribution in tissues. Subsequent experiments were performed in c57bl6 mice, crebh knockout mice, primary hepatocytes and hepg2 cells.

Anaemia is a clinical hallmark of advanced kidney disease, characterized by insufficient erythropoiesis due to inadequate erythropoietin production in the kidney, inflammation and iron. We show that these defects associate with dysregulated expression of genes encoding epo, epor, vegfr1, and iron regulatory proteins. Request pdf hypoxic regulation of erythropoiesis and iron metabolism the kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood. Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body.

Hypoxic regulation of erythropoiesis and iron metabolism request. The intestinal iron absorption is modulated in response to the level of body iron stores and by the amount of iron needed for erythropoiesis. Recent evidence indicates that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Red blood cell production is a finely tuned process that requires coordinated oxygen and iron dependent regulation of cell differentiation and iron metabolism. Swinkels,5 harold tjalsma,5 marco maggiorini,6,8 pierre krayenbuhl, 6 monika rau,1,2 heiko fruehauf,1 kacper a. Epo is a survival, proliferation and differention factor for the erythrocytic progenitors, particularly the colony. Hypoxic stimulation of erythropoiesis requires that additional iron is readily made available for heme synthesis. Epo is a survival, proliferation and differention factor for the erythrocytic progenitors, particularly the. Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Role of the hypoxia inducible factors hif in iron metabolism. Abstract molecular iron metabolism and its regulation are least well understood in the fetal and early postnatal periods of mammalian ontogenic development. Erythropoiesis controls iron homeostasis, by releasing erythroferrone that inhibits hepcidin transcription to increase iron acquisition in iron deficiency, hypoxia and epo treatment.

Haase prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia inducible factor hif, which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. A classic physiologic response to systemic hypoxia is the increase in red blood cell production. Latest advances also reveal a direct titration of the bone morphogenetic proteins by the erythroferrone contributing to liver hepcidin suppression to increase iron availability. We used microarray and other transcriptional analyses to investigate the role of the upc2 and bcr1 transcription factors in controlling expression of genes involved in cell wall metabolism, ergosterol synthesis, and glycolysis during adaptation to hypoxia. Regulation of iron homeostasis by the hypoxiainducible. Iron metabolism, oxygen homeostasis and erythropoiesis are consequently strongly interconnected. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health. The relationship between systemic iron homeostasis and. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 bmp6, hereditary hemochromatosis protein, transferrin receptor 2.

Living organisms have, therefore, evolved sophisticated and tightly regulated mechanisms to control iron uptake, transport, and release. Clinical iron deficiency disturbs normal human responses. Iron is an essential element in all living organisms and is required as a cofactor for oxygenbinding proteins. Hypoxiainducible factor activators in renal anemia. Hepatic hif2 regulates erythropoietic responses to hypoxia. Markers of iron metabolism and erythropoiesis were comprehensively evaluated in 22. Efforts to understand the molecular basis of oxygenregulated 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. Full text induction of erythropoiesis by hypoxiainducible. Its key function in the hypoxic regulation of erythropoiesis is underscored by genetic studies in human populations that live at highaltitude and by mutational analysis of patients with familial erythrocytosis. Robach p, cairo g, gelfi c, bernuzzi f, pilegaard h, vigano a, santambrogio p, cerretelli p, calbet ja, moutereau s, lundby c 2007 strong iron demand during hypoxiainduced erythropoiesis is associated with downregulation of ironrelated proteins and myoglobin in human skeletal muscle. Hypoxiainducible factor1 deficiency results in dysregulated. Two regulatory models have been proposed, both of which may contribute to the regulation of iron absorption. Anemia is a syndrome, resulting from a reduced red cell mass more than two standard deviations from the mean for age, gender and race.

Hypoxia inducible factors hifs orchestrate this response by inducing celltype 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. However, hepcidin suppression at high altitude is not driven by a reduction in iron stores. Hepcidin mrna levels in mouse liver respond to inhibition. Molecular insights into the regulation of iron metabolism. The regulation of hepcidin and its effects on systemic and. New insights into the links between hypoxia and iron. Regulation of erythropoiesis by hypoxiainducible factors. Here, we show that translational regulation of hypoxiainducible factor 2. Iron, anemia, hypoxia, and inflammation were reported to influence hepcidin expression. Jul 24, 2018 the typically hypoxic environment with consequently. When erythropoiesis is stimulated by hypoxia, iron demand in the bone marrow increases. Hepcidin, a key regulator of iron metabolism, decreases intestinal absorption of iron and its release from macrophages. The level of erythropoietic demand regulates the expression of the iron hormone hepcidin and thus iron absorption.

Ineffective erythropoiesis in betathalassemia is characterized by increased iron absorption mediated by downregulation of hepcidin and upregulation of ferroportin. Recent findings the importance of the hepcidinferroportin axis in the modulation of intestinal hif2 to regulate iron absorption. The iron exporter required for iron egress from enterocytes, macrophages, as well as all other iron exporting cells including placental syncytiotrophoblasts and hepatocytes, is ferroportin 1 fpn1, slc40a1, ireg1, or mtp1. Hypoxiainducible factors in erythropoiesis, iron homeostasis. Hypoxic regulation of erythropoiesis and iron metabolism american. Hif2 activation either by hypoxia, pharmacologic means or as a result of mutations induces renal and hepatic epo synthesis, which leads to an increase in serum epo levels and stimulation of erythropoiesis. In addition to regulating iron metabolism, hypoxia and the phdhif pathway stimulate erythropoiesis through direct effects on the bone marrow via stimulation of epo receptor expression, hemoglobin synthesis, 6367 and modulation of stem cell maintenance, lineage differentiation, and maturation.

Hypoxic regulation of erythropoiesis and iron metabolism. When the amount of iron in the body stores decreases. To gain insight into potential hypoxia dependent molecular mechanisms that might control hepcidin expression in iron homeostasis. Heme synthesis depends on iron through its dependence on iron sulfur fes cluster biogenesis. A biomathematical model of human erythropoiesis and iron. Disorders of erythropoiesis,erythrocytes and iron metabolism chapter2regulationoferythropoiesis 47 hsc cmp mep bfumk platelet primitive bfue megacaryocyte cfue red blood cell mature bfue proerythroblast reticulocyte erythroblast cd34 cd33 epor cd71 glycophorin a hladr ckit bfuep bfuem cfue proebl erythroblasts baso i baso ii poly. Iron needs to be tightly regulated, as iron insufficiency induces a hypoferric anemia in mammals, coupled to hypoxia in. Erythropoiesis in animals is a synchronized process of erythroid cell differentiation that depends on successful acquisition of iron. Pdf erythropoiesis, hemoglobin synthesis, and erythroid. Oxygenregulation of erythropoiesis and iron metabolism. To investigate regulation of the expression of hepcidin and other iron related genes, we man. Reciprocal regulation between hepcidin and erythropoiesis and its therapeutic application in erythroid disorders caiyi wanga,b,1, zheng fanga,1, zesen zhua.

Hypoxic regulation of iron homeostasis and bone marrow environment the availability of sufficient amounts of iron is critically important for normal and stressinduced erythropoiesis. Haase investigates the cellular and molecular mechanisms that lead to the development of renal anemia. Hepcidin, the central regulator of iron homoeostasis, is itself regulated by many factors including iron stores, hypoxia, inflammation and erythropoiesis. Request pdf hypoxic regulation of erythropoiesis and iron metabolism the kidney is a highly sensitive oxygen sensor and plays a central role in mediating. Regulation of erythropoietin production jelkmann 2011. May 05, 2010 hypoxic regulation of iron homeostasis and bone marrow environment the availability of sufficient amounts of iron is critically important for normal and stressinduced erythropoiesis. Here, we also provide evidence that hepatocytederived hif2 is involved in the transcriptional regulation of several iron metabolism genes. Diagram of the feedback regulation of erythropoiesis lack of o 2 hypoxia is a stimulus for the synthesis of erythropoietin epo, primarily in the kidneys. Hypoxiainducible factors link iron homeostasis and erythropoiesis. Cell metabolism short article the irp1hif2a axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption sheila a.

The regulation of the response of candida albicans to hypoxic lowoxygen conditions is poorly understood. The lab studies the oxygendependent regulation of erythropoiesis and iron metabolism and its therapeutic targeting for the treatment of renal anemia. Ineffective erythropoiesis and regulation of iron status in. Iron is an essential trace metal involved in oxygen transport, cellular metabolism, dna synthesis, innate immunity, growth, and development. Iron status affects cognitive and physical performance in humans.

Hepatic hif2 regulates erythropoietic responses to. Serum iron levels depend on intestinal absorption from the diet, transport capacity in the blood, recycling of iron released from phagocytosed erythrocytes, and. Hypoxia induces a highly conserved signaling pathway in cells under conditions of low o 2. It limits iron absorption from the intestine and release from macrophages by controlling the synthesis and activity of several iron transport proteins. Iron is recycled thanks to erythrophagocytosis of senescent erythrocytes by macrophages. Because the liver plays a central role in the regulation of iron homeostasis, we hypothesized that hif2 may coordinate epo production with iron metabolism in the liver. Shown is a simplified overview of hypoxic and hifmediated effects on iron metabolism. Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia inducible factor hif, which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Regulation of erythropoiesis by hypoxia inducible factors. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases hifphi prolyl hydroxylase inhibitor stimulate the production of endogenous. Iron is an essential element for normal cellular metabolism and growth as an enzyme cofactor, heme constituent and oxygenation sensor. To gain insight into potential hypoxiadependent molecular mechanisms that might control hepcidin expression in iron homeostasis.