scholarly journals Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 5027-5035 ◽  
Author(s):  
Sara Gardenghi ◽  
Maria F. Marongiu ◽  
Pedro Ramos ◽  
Ella Guy ◽  
Laura Breda ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Absorption ◽  
Regulatory Gene ◽  
Regulatory Genes ◽  
Ineffective Erythropoiesis ◽  
Transfusion Therapy ◽  
Iron Distribution ◽  
Tissue Iron

Abstract Progressive iron overload is the most salient and ultimately fatal complication of β-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in β-thalassemia. We analyzed tissue iron content and iron-regulatory gene expression in the liver, duodenum, spleen, bone marrow, kidney, and heart of mice up to 1 year old that exhibit levels of iron overload and anemia consistent with both β-thalassemia intermedia (th3/+) and major (th3/th3). Here we show, for the first time, that tissue and cellular iron distribution are abnormal and different in th3/+ and th3/th3 mice, and that transfusion therapy can rescue mice affected by β-thalassemia major and modify both the absorption and distribution of iron. Our study reveals that the degree of IE dictates tissue iron distribution and that IE and iron content regulate hepcidin (Hamp1) and other iron-regulatory genes such as Hfe and Cebpa. In young th3/+ and th3/th3 mice, low Hamp1 levels are responsible for increased iron absorption. However, in 1-year-old th3/+ animals, Hamp1 levels rise and it is rather the increase of ferroportin (Fpn1) that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the iron overload of β-thalassemia.

Ineffective Erythropoiesis in β-Thalassemia Is Characterized by Increased Iron Absorption Mediated by down Regulation of Hepcidin and up Regulation of Ferroportin.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1543-1543 ◽  
Author(s):  
Sara Gardenghi ◽  
Maria Marongiu ◽  
Pedro Ramos ◽  
Ella Guy ◽  
Laura Breda ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Absorption ◽  
Hematological Parameters ◽  
Iron Concentration ◽  
Dry Weight ◽  
Heme Iron ◽  
Ineffective Erythropoiesis ◽  
Transfusion Therapy ◽  
Expression Levels

Abstract Progressive iron overload occurs in β-thalassemia as a result of increased gastrointestinal absorption. Our goal is to investigate the relationship between ineffective erythropoiesis (IE), iron-related genes and organ iron distribution in mice that exhibit levels of anemia consistent with thalassemia intermedia (th3/+) and major (th3/th3), as we described previously. The th3/th3 mice die in 8 weeks due to severe anemia but can be rescued by transfusion therapy. We analyzed up to 90 animals at 2, 5 and 12 months, as appropriate. We monitored various hematological parameters, tissue iron content and quantitative-PCR levels of Hamp, Fpn1, Smad4, Cebpa, Hfe, Tfr1 and other genes involved in iron metabolism in liver, spleen, kidney, heart and duodenum. At 2 months, th3/th3 mice had the highest total body iron content and highest degree of IE. The total iron was 53.6±21.0, 406.1±156.1, 657.7±40.3 μg in the spleen, and 107.5±35.7, 208.5±24.9 and 1298.7±427.5 μg in the liver of +/+, th3/+ and th3/th3, respectively (n≥5 per genotype). However, if the organ size was not taken in account, the iron concentration in the spleen of th3/+ was higher, in average, than that of th3/th3 mice (3.8±1.5 and 2.9±0.5 μg/mg), while in the liver was the opposite (0.6±0.1 and 5.1±2.0 μg/mg of dry weight, P<0.001). Heme and non-heme iron analyses provided similar results. Surprisingly, the distribution of iron within organs also differed. In th3/+ mice, the hepatic iron was almost exclusively located in Kupffer cells, whereas in th3/th3 mice in parenchymal cells. Our data suggest that Hamp is responsible for the increased iron absorption, being reduced to 20% and 70% in 2 month-old th3/+ and th3/th3 mice compared to +/+ animals (P<0.001). Hfe was reduced by 50% (P<0.05) in the liver of the animals that expressed low Hamp levels, indicating that Hfe could be directly responsible for Hamp regulation or share the same regulatory pathway. Low levels of Smad4 and Cebpa were observed only in the liver of mice with the lowest Hamp expression (P<0.05), indicating that these proteins might contribute to further decreased Hamp synthesis. In addition, while Tfr1 in th3/+ mice was 40% lower in the liver, it was up-regulated (400%) in th3/th3 mice (P<0.001), which may explain why iron is increased more in the liver of th3/th3 mice. In 5 and 12 month-old th3/+ mice, the surprising observation was the normal expression level of Hamp. However, in the duodenum, the Fpn1 RNA and protein levels were augmented (300%, P<0.001). In transfused th3/+ and th3/th3 animals, Hamp, Hfe, Cbpa and Smad4 expression levels were normalized or increased, while Tfr1 was down-regulated in both groups, which may explain the increased splenic iron deposition in these animals. Our data suggest that IE, together with the relative expression levels of Hamp and Tfr1, is largely responsible for the organ iron overload observed in young thalassemic mice. However, in older mice, it is the increase of Fpn1 levels in the duodenum that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the genesis of iron overload in β-thalassemia.

scholarly journals Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 5021-5029 ◽  
Author(s):  
Antonella Nai ◽  
Alessia Pagani ◽  
Giacomo Mandelli ◽  
Maria Rosa Lidonnici ◽  
Laura Silvestri ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Absorption ◽  
Therapeutic Option ◽  
Iron Loading ◽  
Proof Of Concept ◽  
Ineffective Erythropoiesis ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Partial Correction

Abstract Inappropriately low expression of the key iron regulator hepcidin (HAMP) causes iron overload in untransfused patients affected by β-thalassemia intermedia and Hamp modulation provides improvement of the thalassemic phenotype of the Hbbth3/+ mouse. HAMP expression is activated by iron through the bone morphogenetic protein (BMP)–son of mothers against decapentaplegic signaling pathway and inhibited by ineffective erythropoiesis through an unknown “erythroid regulator.” The BMP pathway is inactivated by the serine protease TMPRSS6 that cleaves the BMP coreceptor hemojuvelin. Here, we show that homozygous loss of Tmprss6 in Hbbth3/+ mice improves anemia and reduces ineffective erythropoiesis, splenomegaly, and iron loading. All these effects are mediated by Hamp up-regulation, which inhibits iron absorption and recycling. Because Hbbth3/+ mice lacking Tmprss6 show residual ineffective erythropoiesis, our results indicate that Tmprss6 is essential for Hamp inhibition by the erythroid regulator. We also obtained partial correction of the phenotype in Tmprss6 haploinsufficient Hbbth3/+ male but not female mice and showed that the observed sex difference reflects an unequal balance between iron and erythropoiesis-mediated Hamp regulation. Our study indicates that preventing iron overload improves β-thalassemia and strengthens the essential role of Tmprss6 for Hamp suppression, providing a proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in this condition.

Potential Use of Jak2 Inhibitors to Limit Ineffective Erythropoiesis and Reverse Splenomegaly in β-Thalassemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1877-1877
Author(s):  
Luca Melchiori ◽  
Ella Guy ◽  
Ilaria Libani ◽  
Raffaella Schirò ◽  
Pedro Ramos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Iron Overload ◽  
Iron Absorption ◽  
Blood Transfusions ◽  
Spleen Size ◽  
Thalassemia Intermedia ◽  
Ineffective Erythropoiesis ◽  
Transfusion Therapy ◽  
Jak2 Inhibitor ◽  
Jak2 Inhibitors

Abstract β-Thalassemia intermedia and major are characterized by ineffective erythropoiesis (IE), requiring sporadic or chronic blood transfusions, respectively. Some of the major consequences of IE are extra-medullary hematopoiesis (EMH), splenomegaly and systemic iron overload mediated by transfusion therapy and down-regulation of hepcidin. Using mouse models of β-thalassemia intermedia (th3/+) and major (th3/th3), and human specimens we investigated IE in this disorder. Th3/+ and th3/th3 erythroid cells were analyzed with respect to rates of apoptosis and degrees of cell proliferation and differentiation. We found that there was both a relative and absolute expansion of the immature erythroid progenitor cell fraction in thalassemic mice compared to cells in the final stages of differentiation. Further investigation of the thalassemic erythroid cells in vivo and in vitro indicated that a larger number of the thalassemic cells are associated with the phosphorylated form of the Jak2 protein kinase than in normal mice. In fact, their proliferation was prevented by TG101209, a Jak2 inhibitor. Similar compounds are currently utilized or being considered for use in the treatment of myeloproliferative diseases such as polycythemia vera. In order to assess the potential of Jak2 inhibitors in limiting IE in β-thalassemia, we administered TG101209 to th3/+ mice. We found that both 10 and 18 days of treatment were sufficient to dramatically reduce the spleen size and the percentage of immature erythroid progenitors therein compared with administration of a placebo. However, these changes were associated with decreasing hemoglobin levels (Blood, 2008, 112:875–85). We speculated that this problem could be overcome by administration of blood transfusions during treatment, an extension of current management in thalassemia as noted above. To test this hypothesis, we administered TG101209 to th3/th3 mice in conjunction with regular blood transfusions. Administration of TG101209 to transfused th3/+ mice is in progress. Our preliminary data on th3/th3 mice indicates that simultaneous administration of TG101209 and transfused blood not only reverses splenomegaly, but also results in higher Hb levels (N ≥ 3). The increased hemoglobin levels observed, compared to those in mice treated with transfusion therapy alone, suggest that the use of Jak2 inhibitors may reduce the amount of blood per transfusion and/or the rate of transfusion required in thalassemia. Since the increased iron absorption in thalassemic mice is a direct consequence of IE, treatment with TG101209 could also be beneficial in ameliorating this process. According to several observations, suppression of erythropoiesis should lead to increased Hamp1 expression in the presence of iron overload. Therefore, under conditions of Jak2 inhibition, Hamp1 transcription is expected to increase. To test this hypothesis we are currently analyzing organ iron levels and the expression of iron-related genes in drug-treated mice. In conclusion, although our study does not exclude a role for apoptosis in the IE of β-thalassemia, we have demonstrated that increased cell proliferation and limited cell differentiation play a significant role in this process. Moreover, we show for the first time that a Jak2 inhibitor is effective in decreasing the spleen size of thalassemic mice. This could represent a completely new approach to the treatment of splenomegaly in β-thalassemia patients, perhaps coupled with blood transfusion. That administration of a Jak2 inhibitor reverses splenomegaly and also ameliorates the degree of iron overload could provide an opportunity to gain new insight into the dynamic processes of iron absorption and erythropoiesis in this pathological condition.

scholarly journals Ferroportin and Erythroid Cells: An Update

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Luciano Cianetti ◽  
Marco Gabbianelli ◽  
Nadia Maria Sposi
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Therapeutic Intervention ◽  
Erythroid Differentiation ◽  
Beta Thalassemia ◽  
Ineffective Erythropoiesis ◽  
Tissue Iron ◽  
Human Disorders ◽  
The Relationship

In recent years there have been major advances in our knowledge of the regulation of iron metabolism that have had implications for understanding the pathophysiology of some human disorders like beta-thalassemia and other iron overload diseases. However, little is known about the relationship among ineffective erythropoiesis, the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. The principal aim of this paper is an update about the role of Ferroportin during human normal and pathological erythroid differentiation. Particular attention will be given to beta-thalassemia and other diseases with iron overload. Recent discoveries indicate that there is a potential for therapeutic intervention in beta-thalassemia by means of manipulating iron metabolism.

Hepcidin as a Therapeutic Tool to Limit Iron Overload and Improve Anemia In β-Thalassemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1009-1009 ◽  
Author(s):  
Sara Gardenghi ◽  
Pedro Ramos ◽  
Cindy N. Roy ◽  
Nancy C. Andrews ◽  
Elizabeta Nemeth ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Iron Overload ◽  
Life Span ◽  
Red Blood Cells ◽  
Iron Content ◽  
Blood Cells ◽  
Reactive Oxygen ◽  
Red Cell ◽  
Oxygen Species ◽  
Ineffective Erythropoiesis

Abstract Abstract 1009 The principal regulator of iron homeostasis, the hepatic peptide hepcidin (Hamp), degrades the iron-transport protein ferroportin (Fpn) localized on absorptive enterocytes, hepatocytes and macrophages. Low Hamp expression has been associated with iron overload in patients and mice affected by β-thalassemia intermedia (th3/+). Our hypothesis is that more iron is absorbed than required for erythropoiesis in β-thalassemia. Therefore, we propose that limiting the dietary iron intake of th3/+ mice either by feeding them a low iron diet or increasing their Hamp expression will have a beneficial effect on iron overload with no effects on erythropoiesis. In particular, since Hamp expression is low in β-thalassemia, a moderate increase of Hamp expression should not interfere with erythropoiesis by preventing release of iron from macrophages. However, we predict that very high levels of Hamp expression will limit the recycling of iron from macrophages, thereby exacerbating the anemia. We first analyzed wt and th3/+ mice fed diets containing a physiological amount of iron (35 ppm) or low iron (2.5 ppm) for 1 and 5 months. These mice were then compared to wt and th3/+ mice expressing a transgenic Hamp (THamp and THamp/th3, respectively). In wt mice, the low-iron diet decreased tissue iron levels leading to anemia (Hb: 14.6±0.7 g/dL and 8.6±2.4 g/dL at 1 and 5 months, respectively). In th3/+ mice fed the low-iron diet, the amount of iron in the liver and spleen decreased over time and after 5 months was 10 times lower than at the beginning of treatment. However, in this case the low-iron diet did not worsen the anemia, (Hb: 8.2±1.3 g/dL vs. 7.8±1.8 g/dL at 1 and 5 months, respectively). In the case of THamp and THamp/th3 mice, we stratified those animals whose transgenic Hamp expression was moderate (2-4 higher) or high (>4 times higher) compared to the endogenous Hamp expression in control mice. In THamp animals expressing a moderate level of Hamp, the total iron content of the liver was decreased (65±21 μg vs. 131±31 μg in wt controls) while no significant changes were detected in the spleen. THamp mice also exhibited anemia (Hb: 11.2±1.8 g/dL vs. 13.9±1.1 g/dL at 1 month). The iron content of the liver and spleen was reduced in THamp/th3 (127±86 μg vs. 234±49 μg and 131±88 μg vs. 271±74 μg, respectively, compared to th3/+ controls), while their hematological values were dramatically improved. Splenomegaly was also significantly reduced. Similar findings were observed at 5 months. Looking at animals expressing high levels of transgenic Hamp, both THamp and THamp/th3 mice exhibited vast accumulations of iron in macrophages, profound anemia, reticulocytosis and increased splenomegaly, confirming that high levels of Hamp block iron recycling and are detrimental to erythropoiesis. Interestingly, in THamp/th3 mice expressing a moderate level of Hamp we observed that the increase in hemoglobin levels was associated with increased red cell numbers but reduced mean corpuscular hemoglobin levels. Paradoxically, this could indicate that reduction of the anemia in THamp/th3 mice is mediated by decreased heme synthesis. α-Globin/heme aggregates lead to ineffective erythropoiesis and a limited red cell life span by producing reactive oxygen species and altering the structure of red cell membranes. Compared to th3/+ mice, THamp/th3 mice exhibited reduced heme contents, insoluble membrane-bound α-globins and reactive oxygen species resulting in an increased life span and more normal morphology of their red blood cells. While the number of red blood cells was increased, the number of reticulocytes, and the total number of erythroid precursors in the spleen were reduced. This was associated with a reduction in reactive oxygen species. Cell cycle analysis of the erythroid cells at different stages of differentiation, expression of heme related proteins and synthesis of α- and β-globin chains in THamp/th3 mice is in progress. Overall, this study indicates that use of hepcidin might be effective in reducing iron overload and improving erythropoiesis in β-thalassemia thereby limiting toxicity due to heme not incorporated into the adult hemoglobin tetramer. In conclusion, we believe this study provides the first evidence that hepcidin could be utilized for the treatment of abnormal iron absorption in β-thalassemia and other related disorders, with additional beneficial effects on ineffective erythropoiesis, splenomegaly and anemia. Disclosures: Nemeth: Intrinsic Life Sciences: Employment, Membership on an entity's Board of Directors or advisory committees.

RNAi-Mediated Inhibition of Tmprss6 Ameliorates Anemia and Secondary Iron Overload in a Mouse Model of β-Thalassemia Intermedia and Decreases Iron Overload in Hfe−/− Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1018-1018
Author(s):  
Paul J Schmidt ◽  
Anoop K Sendamarai ◽  
Ivanka Toudjarska ◽  
Tim Racie ◽  
Jim S Butler ◽  
...  
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Iron Absorption ◽  
Disease Phenotype ◽  
Ineffective Erythropoiesis ◽  
Employment Equity ◽  
Liver Iron ◽  
Secondary Iron Overload ◽  
Equity Ownership ◽  
Low Levels

Abstract Abstract 1018 β-Thalassemia intermedia (TI), an inherited hemoglobinopathy caused by partial loss of β-globin synthesis, is characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis as well as secondary iron overload. Hereditary hemochromatosis (HH) is most frequently caused by mutations in HFE and is marked by excess uptake of dietary iron with concomitant tissue iron overload. In both diseases, increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (encoded by Hamp1). The membrane serine protease Matriptase-2 (encoded by Tmprss6) attenuates BMP-mediated Hamp1 induction by cleaving the BMP co-receptor, hemojuvelin. Previously, it has been shown that elevating Hamp1 expression by genetic inactivation of Tmprss6 reduces disease severity in the Hbbth3/+ mouse model of TI and prevents iron overload in Hfe−/− mice. Therefore, a therapeutic approach comprising specific inhibition of Tmprss6 could prove efficacious in TI and HH. Here we show that systemic administration of a potent lipid nanoparticle (LNP) formulated siRNA directed against Tmprss6 leads to >80% inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ and Hfe−/− mice with concomitant >2-fold elevation in Hamp1 expression. In the TI model, Tmprss6 silencing leads to ∼30% reductions in serum iron and non-heme liver iron. In Hfe−/− mice, serum iron and non-heme liver iron are similarly reduced, and Perls staining of peri-portal iron is diminished. Remarkably, the partial iron restriction induced by Tmprss6 inhibition in Hbbth3/+ mice leads to dramatic improvements in the hematological aspects of the disease phenotype: the severity of the anemia is decreased as evidenced by an approximately 1 g/dL increase in total hemoglobin and a 50% decrease in circulating erythropoietin levels. As in the human disease, Hbbth3/+ mice exhibit the hallmarks of ineffective erythropoiesis including splenomegaly, decreased erythrocyte survival and marked reticulocytosis. Treatment with LNP formulated Tmprss6 siRNA leads to a dramatic 2–3 fold decrease in spleen size, a 3–4 fold decrease in reticulocyte counts and a >7-day increase in RBC half-life. Histological analysis of spleens from Tmprss6 siRNA treated animals demonstrates restoration of normal splenic architecture, as well as a reduction in the number of Tfr1-positive erythrocyte precursors in the spleen. Furthermore, as evidenced by the near normalization of blood smears, the overall quality of erythropoiesis in treated animals is vastly improved. Taken together, these data demonstrate that RNAi-mediated silencing of liver Tmprss6 elevates Hamp1 expression and reduces iron overload in both TI and HH model mice. More significantly, Tmprss6 siRNA treatment ameliorates all aspects of the disease phenotype in the TI mouse model. These results support the development of an RNAi therapeutic targeting TMPRSS6 for the treatment of TI, HH and potentially other disorders characterized by excess iron absorption due to physiologically inappropriately low levels of hepcidin. Disclosures: Racie: Alnylam Pharmaceuticals: Employment. Butler:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership. Bumcrot:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership.

Dietary Supplementation with Genistein Increases Hepcidin Expression in Wild Type Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3208-3208
Author(s):  
Aileen W. Zhen ◽  
Josephine Volovetz ◽  
Paula G. Fraenkel
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Absorption ◽  
Small Scale ◽  
Iron Release ◽  
Liver Iron ◽  
Transcript Levels ◽  
Intestinal Iron Absorption ◽  
Hepcidin Expression ◽  
Liver Iron Content

Abstract Abstract 3208 Iron overload is an important cause of morbidity and death in patients with hemoglobinopathies, transfusion-dependent anemias, and hereditary hemochromatosis. As humans have no means of excreting iron, regulation of iron homeostasis depends on limiting intestinal iron absorption and optimizing iron release from macrophages to developing erythrocytes. Hepcidin, a peptide hormone produced in the liver, modulates intestinal iron absorption and macrophage iron release via effects on ferroportin. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. We conducted a small-scale chemical screen and found that the isoflavone genistein, a major dietary component of soybeans, enhanced Hepcidin transcript levels in zebrafish embryos. Furthermore genistein treatment increased Hepcidin transcript levels and Hepcidin promoter activity in human hepatocytes (HepG2 cells) in a Stat3 and Smad4-dependent manner. To evaluate genistein's effect in a mammalian model, we placed groups of 4 four-week old male C57BL/6 mice on an iron-sufficient, low soy diet (AIN93G containing 35 mg of iron/kg) supplemented with 0, 250, or 500 mg of genistein per kg of food for 7 weeks, and then sacrificed the animals for analysis. Plasma genistein levels (mean±SE) at the time of sacrifice were 0.015±0.015, 0.52±0.173, and 2.07±0.65 micromolar, respectively. Compared to mice not treated with genistein, the 250 mg/kg dose produced a significant increase in hepatic Hepcidin (HAMP1) transcript levels (1.49±0.10 vs 0.93±0.10, p=0.01), while the 500 mg/kg dose did not. Although liver iron content, spleen iron content, and weight gain were not significantly different among the groups, the ratio of Hepcidin expression to liver iron content was significantly increased in the animals treated with genistein 250 mg/kg compared to controls (0.013±0.0009 vs 0.0074±0.00068, p=0.0068). In conclusion, genistein is the first orally administered small molecule experimental drug shown to increase Hepcidin transcript levels in vivo. Future experiments will evaluate the effects of genistein on genetic models of iron overload syndromes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Iron Overload in the Face of Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-38-SCI-38
Author(s):  
Yatrik Shah
Keyword(s):  
Transcription Factors ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Absorption ◽  
Conflicts Of Interest ◽  
Iron Accumulation ◽  
Cell Disease ◽  
Divalent Metal Transporter 1 ◽  
Tissue Iron

Abstract Several distinct congenital disorders can lead to tissue-iron overload with anemia including β-thalassemia and sickle cell disease. We show that intestinal absorption of iron is highly increased and significantly contributes to tissue iron accumulation in these disorders. The present work describes a novel pathway by which oxygen sensing transcription factors are highly upregulated in iron overload anemias and are subsequently essential for the increase intestinal iron absorption. Oxygen signaling is mediated through well-conserved hypoxia driven transcription factors, hypoxia-inducible factor (HIF)1a and HIF2a. In the intestine, HIF2a directly activates divalent metal transporter 1 (DMT1), duodenal ferric reductase (DcytB), and Fpn1, which are iron transporters critical for adaptive changes in iron absorption. We demonstrate that HIF2a and its downstream target gene, DMT1 are essential for iron accumulation in mouse models of β-thalassemia and sickle cell disease. Furthermore, studies of thalassemic mouse model with established iron overload demonstrated that loss of intestinal HIF2a and DMT1 signaling led to decreased tissue iron accumulation in the livers. Interestingly, disrupting intestinal HIF2a not only improves tissue iron accumulation, but a marked improvement of anemia was also observed. These novel findings suggests that inhibition of HIF2a signaling pathway could be a novel and robust treatment strategy for several conditions that cause iron overload with anemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ameliorating Iron Overload in Intestinal Tissue of Adult Male Rats: Quercetin vs Deferoxamine

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Arwa A. El-Sheikh ◽  
Shimaa Hamed Ameen ◽  
Samaa Salah AbdEl-Fatah
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Adult Male ◽  
Caspase 3 ◽  
Iron Chelation ◽  
Male Rats ◽  
Albino Rats ◽  
Tissue Iron ◽  
Small Intestinal

Objective. The aim of our study is to compare the role of the new natural alternative (Quercetin) with the current iron-chelation therapy (Deferoxamine (DFO)) in the effect of iron overload on small intestinal tissues and to investigate the possible underlying molecular mechanisms of such toxicity. Methods. Forty-two adult male albino rats were divided into six groups: control groups, DFO, Quercetin, iron overload, iron overload+DFO, and iron overload+Quercetin groups. Animals received daily intraperitoneal injection of Deferoxamine (125 mg /kg), Quercetin (10 mg/kg), and ferric dextran (200 mg/kg) for 2 weeks. Results. Iron overloaded group showed significant increase in serum iron, total iron binding capacity (TIBC), transferrin saturation percentage (TS %) hepcidin (HEPC), serum ferritin, nontransferrin bound iron (NTBI), and small intestinal tissues iron levels. Iron overload significantly increased the serum oxidative stress indicator (MDA) and reduced serum total antioxidant capacity (TAC). On the other hand, iron overload increased IL6 and reduced IL10 in small intestinal tissues reflecting inflammatory condition and increased caspase 3 reactivity indicating apoptosis and increased iNOs expressing cell indicting oxidative stress especially in ileum. In addition, it induced small intestinal tissues pathological alterations. The treatment with Quercetin showed nonsignificant differences as compared to treatment with DFO that chelated the serum and tissue iron and improved the oxidative stress and reduced tissue IL6 and increased IL10 and decreased caspase 3 and iNOs expressing cells in small intestinal tissues. Moreover, it ameliorated the iron overload induced pathological alterations. Conclusion. Our study showed the potential role of Quercetin as iron chelator like DFO in case of iron overload induced small intestinal toxicity in adult rats because of its serum and tissue iron chelation, improvement of serum, and small intestinal oxidative stress, ameliorating iron induced intestinal inflammation, apoptosis, and histopathological alterations.

Kinetic of Iron Absorption and Expression of Iron Related Genes in Beta-Thalassemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3846-3846
Author(s):  
Laura Breda ◽  
Sara Gardenghi ◽  
Ella Guy ◽  
Ninette Amariglio ◽  
Konstantin Adamsky ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Absorption ◽  
Globin Gene ◽  
Active Form ◽  
Beta Thalassemia ◽  
Post Transplantation ◽  
Divalent Metal Transporter 1 ◽  
Hematopoietic Stem ◽  
Divalent Metal Transporter

Abstract We generated the first transplantable adult mouse models of beta-thalassemia intermedia and major by infusing mouse hematopoietic-fetal-liver cells (HFLC) heterozygous or homozygous for a deletion of the beta-globin gene (respectively with th3/+ and th3/th3 cells) into lethally irradiated congenic C57BL/6 mice. Six to 8 weeks post transplantation, mice transplanted with th3/+ HFLCs show 7 to 9 g/dL of hemoglobin levels, splenomegaly, abnormal red cells and increased iron overload. Mice transplanted with th3/th3 HFLCs, unless blood transfused, die 8 to 10 weeks after engraftment showing profound anemia, massive splenomegaly and very rapid and dramatic iron overload. For this reason, we began a systematic study to compare iron content and the expression level of iron related genes in normal and thalassemic mice of varying ages and sex in different organs (liver, duodenum, spleen, kidney and heart). In liver, we observed that iron content increases proportionally with the level of anemia, age and if the blood transfusion is included. We are currently analyzing the other organs. The expression of hepcidin, ferroportin, Hfe, ferritin, transferrin, transferrin-receptor 1 and 2, ceruloplasmin, divalent metal transporter 1 and hemojuvelin are being tested also in all these organs. In particular, we observed that hepcidin is dramatically downregulated in liver of beta-thalassemic animals. Our hypothesis is that low expression of this gene leads to high iron content in these animals. We intend to demonstrate that administration or increasing hepcidin levels of this peptide can prevent iron absorption in beta-thalassemia. We developed two alternative strategies to test our hypothesis. In the first one, we synthesized the active form of the mouse hepcidin peptide that will be administered intraperitoneally to mice affected by beta-thalassemia. In the second, lentiviral vectors have been generated in order to constitutively secrete hepcidin in the bloodstream of animals affected by beta-thalassemia. These vectors were introduced into hematopoietic stem cells derived from mouse embryos of normal and mice affected by beta-thalassemia and engrafted in myeolablated normal mice. The engrafted mice express hepcidin 6 weeks post transplantation by RT PCR. These animals, along with the animals in which hepcidin will be administrated intraperitoneally, will be analyzed at the endpoint of the experiment (&gt; 4 months) for their hematological values and iron content to see if the use of hepcidin can be used to prevent excessive iron absorption in beta-thalassemia.

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