Quantitative analysis of dietary iron utilization for erythropoiesis in response to body iron status

Matsuo-Tezuka, Yukari; Noguchi-Sasaki, Mariko; Kurasawa, Mitsue; Yorozu, Keigo; Shimonaka, Yasushi

doi:10.1016/j.exphem.2016.02.005

Cited by 6 publications

(4 citation statements)

References 35 publications

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“…In rodents under stress erythropoiesis, extramedullary hematopoiesis is induced and splenomegaly is often observed because of the expansion of erythroid lineage cells. As previously reported [ 7 ], C.E.R.A. also induced extramedullary hematopoiesis accompanied by splenomegaly.…”

Section: Resultssupporting

confidence: 84%

“…Immature erythroblasts are induced to transcribe erythroid-specific 5-aminolevulinic acid synthase, the key enzyme of heme synthesis, which in turn triggers subsequent hemoglobin synthesis, leading to maturation of erythroblasts into erythrocytes [ 24 ]. As shown in our previous study [ 7 ], C.E.R.A. also stimulates hemoglobin synthesis partly using dietary iron, as assessed using an 57 Fe-substituted diet and the ICP-MS platform.…”

Section: Resultsmentioning

confidence: 80%

“…Our recent study, combining 57 Fe-labeling with ICP-MS technology, has provided quantitative analysis of dietary iron utilization for hemoglobin synthesis under stress erythropoiesis induced by C.E.R.A. administration in mice [ 7 ]. Based on the analysis of 57 Fe-iron incorporation by ICP-MS, we were able to quantitatively observe not only the dynamics of dietary iron utilization for hemoglobin synthesis but also dietary iron distribution among tissues.…”

Section: Introductionmentioning

confidence: 99%

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Visualization of⁵⁷Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging

Kihara¹,

Matsuo-Tezuka²,

Noguchi-Sasaki³

et al. 2017

J. Am. Soc. Mass Spectrom.

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Epoetin beta pegol (continuous erythropoiesis receptor activator; C.E.R.A.), or methoxy-polyethylene glycol-modified epoetin beta, is a long-acting erythropoiesis stimulating agent (ESA) that effectively maintains hemoglobin levels. It promotes proliferation of erythroid progenitor cells in hematopoietic organs and leads to increased reticulocyte and hemoglobin levels. However, the detailed erythropoietic effects of various ESAs on their target organs have yet to be clarified, and new approaches are needed to analyze tissue iron localization with structural information. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) techniques are widely used in basic pharmaceutical research. High-resolution Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) imaging enables the spatial mapping and identification of biomolecules. In this study, mice administered with C.E.R.A. were fed a diet containing the stable iron isotope 57Fe. The 57Fe-heme+ isotopic fine structure peak (m/z 617.1772) was separated from the non-labeled heme+ isotopic peak (Δ0.0029) by FTICR-MS with a resolving power of more than 500,000. We optimized the platform to analyze the distribution of 57Fe-heme in the spleen using MALDI FTICR-MS imaging. The combination of the ultrahigh resolution power of FTICR-MS and a stable isotope labeling technique has the potential to be very effective in basic pharmaceutical research. Graphical Abstractᅟ Electronic supplementary materialThe online version of this article (doi:10.1007/s13361-017-1768-y) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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Visualization of⁵⁷Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging

Kihara¹,

Matsuo-Tezuka²,

Noguchi-Sasaki³

et al. 2017

J. Am. Soc. Mass Spectrom.

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“…The MCV elevation was higher in the nonanemic control mice than in ISAM mice ( Figure 4 B), indicating that renal EPO induction was needed to fully activate erythropoiesis by GSK360A, in agreement with the data on plasma EPO concentrations ( Figure 1 A). As ESA administration was previously reported to increase MCV without significant impacts on the other erythropoietic parameters in normal mice, 34 GSK360A treatment significantly upregulated MCV in the control mice without altering the erythrocyte counts or hemoglobin concentrations ( Figure 4 B). These data demonstrate that the erythropoietic effects of HIF-PHIs are attenuated by renal EPO deficiency.…”

Section: Resultssupporting

confidence: 52%

Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice

et al. 2023

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The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients suffering from kidney disease. However, the roles of the liver in the HIF-PHI-mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Additionally, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys.

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The effect of frequency of C.E.R.A. administration on the contribution of dietary iron for erythropoiesis

et al. 2017

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Erythropoiesis-stimulating agents are among the therapeutic options for renal anemia. Under erythropoietic stimulation, the synthesis of hemoglobin requires a large amount of iron, which is supplied both from absorption of dietary iron and the mobilization of stored iron. However, under iron-loading conditions, dietary iron absorption is suppressed via down-regulation of duodenal iron transporters. Because the contribution of dietary iron is essential for erythropoiesis, we aimed to investigate the conditions in which dietary iron is efficiently used for erythropoiesis. To quantify the contribution of dietary iron for erythropoiesis, we labelled dietary iron using the stable iron isotope Fe, and assessedFe-derived hemoglobin synthesis under erythropoietic stimulation by C.E.R.A. (Continuous Erythropoietin Receptor Activator) and iron loading in mice. Our results show that the contribution of dietary iron to erythropoiesis is not changed by different increments of C.E.R.A. dose. However, iron loading suppressed the contribution of dietary iron to erythropoiesis. To confirm these results under conditions mimicking clinical settings, we compared single and intermittent administration of C.E.R.A. in mice under both physiological and iron-loaded conditions, and found that the contribution of dietary iron to erythropoiesis is more strongly affected by body iron status than by erythropoietic stimulation.

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Quantitative analysis of dietary iron utilization for erythropoiesis in response to body iron status

Cited by 6 publications

References 35 publications

Visualization of⁵⁷Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging

Visualization of⁵⁷Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging

Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice

The effect of frequency of C.E.R.A. administration on the contribution of dietary iron for erythropoiesis

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Quantitative analysis of dietary iron utilization for erythropoiesis in response to body iron status

Cited by 6 publications

References 35 publications

Visualization of57Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging

Visualization of57Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging

Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice

The effect of frequency of C.E.R.A. administration on the contribution of dietary iron for erythropoiesis

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Visualization of⁵⁷Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging

Visualization of⁵⁷Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging