Erythropoietin stimulation decreases hepcidin expression through hematopoietic activity on bone marrow cells in mice

Sasaki, Yoshiyuki; Noguchi-Sasaki, Mariko; Yasuno, Hideyuki; Yorozu, Keigo; Shimonaka, Yasushi

doi:10.1007/s12185-012-1217-4

Cited by 47 publications

(36 citation statements)

References 29 publications

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“…For example, changes in erythropoietic activity have been shown to modulate liver hepcidin mRNA expression during anemia in an erythropoietinand bone marrow activity-dependent manner. [40][41][42] Phlebotomy-induced acute anemia reduced hepcidin-1 liver mRNA. 4 Concordant with these data, our immunoassay measured a 2.3-to 3.6-fold decrease in hepcidin-1 in males and females, in serum and urine 3 days after blood collection.…”

Section: Discussionmentioning

confidence: 99%

A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis

et al. 2014

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Section: Discussionmentioning

confidence: 99%

A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis

et al. 2014

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“…[39][40][41] In addition to direct suppression of hepcidin by erythropoiesis, HIF mechanisms independent of erythropoiesis have also been implicated in decreasing hepcidin, 42 although this view is somewhat controversial. 43 Pharmacologic inhibition of HIF-prolyl hydroxylase has been shown to stimulate EPO production in both animal models 26 and in humans [27][28][29][30] and to reduce circulating levels of hepcidin.…”

Section: Discussionmentioning

confidence: 99%

“…In the HDD study, no changes were noted in hepcidin concentrations in either the 5-mg GSK1278863 arm or the rhEPO control arm. Because rhEPO has been reported to suppress hepcidin, 40,41 mean hepcidin concentrations may have already been suppressed before randomization in the HDD study because all patients were receiving rhEPO. Consistent with this hypothesis, dose arms in which GSK1278863 was ineffective in maintaining mean hemoglobin (0.5 mg and 2 mg) demonstrated increases in mean hepcidin concentrations after patients were switched from rhEPO.…”

Section: Discussionmentioning

confidence: 99%

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

Holdstock

Meadowcroft

et al. 2016

Journal of the American Society of Nephrology

174

234

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Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dosedependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD. 27: 123427: -124427: , 201627: . doi: 10.1681 Advanced CKD is frequently associated with anemia 1,2 and its pathogenesis is multifactorial, inclusive of a relative deficiency of erythropoietin (EPO) and impaired absorption and utilization of iron. 3 Current guidelines and recommendations for anemia management in CKD advise treatment with supplemental iron and recombinant human erythropoietins (rhEPOs) if appropriate. rhEPO therapy led to a correction of hemoglobin levels in the majority of dialysis patients 12 and a reduction in the need for red blood cell transfusions. 12 However, several large randomized trials of rhEPO have reported adverse cardiovascular outcomes. The Normal Hematocrit Study, which aimed to normalize hematocrit at 42% versus maintaining it at 30%, was terminated early because of concerns from the independent data monitoring committee around the higher all-cause mortality rate in the normal hematocrit arm compared with the low hematocrit arm, even though the prespecified termination criterion of an overall 5% significance was not met. The Correction of Hemoglobin and Outcomes in Renal Insufficien...

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“…6 BMP6, 7,8 a member of the transforming growth factor-b superfamily, binds to a complex of BMP receptors and the co-receptor hemojuvelin (HJV), 9 leading to the phosphorylation of the SMAD1/5/8 proteins, which translocate to the nucleus after complexing with SMAD4. 10 When iron requirements of erythroid progenitor cells are increased, hepcidin expression is repressed by one or several circulating erythroid factors produced by the bone marrow (BM), 11 in order to increase dietary iron absorption and release iron stored in hepatocytes and macrophages. Although several candidates have been proposed, such as growth differentiation factor 15 (GDF15) 12 and twisted gastrulation BMP signaling modulator 1 (TWSG1), 13 it has been recently demonstrated that erythroferrone (ERFE) 14 is the circulating erythroid factor responsible for hepcidin suppression in acute response to erythroid stress.…”

Section: Introductionmentioning

confidence: 99%

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

Nai

Rubio

Campanella

et al. 2016

Blood

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Key Points• Hyperactivation of the BMP-SMAD pathway blunts EPO-mediated hepcidin inhibition.• Lack of BMP-SMAD pathway inhibition by matriptase-2 abrogates the ERFEmediated hepcidin suppression in response to EPO.Hepcidin, the main regulator of iron homeostasis, is repressed when erythropoiesis is acutely stimulated by erythropoietin (EPO) to favor iron supply to maturing erythroblasts. Erythroferrone (ERFE) has been identified as the erythroid regulator that inhibits hepcidin in stress erythropoiesis. A powerful hepcidin inhibitor is the serine protease matriptase-2, encoded by TMPRSS6, whose mutations cause iron refractory iron deficiency anemia. Because this condition has inappropriately elevated hepcidin in the presence of high EPO levels, a role is suggested for matriptase-2 in EPO-mediated hepcidin repression. To investigate the relationship between EPO/ERFE and matriptase-2, we show that EPO injection induces Erfe messenger RNA expression but does not suppress hepcidin in Tmprss6 knockout (KO) mice. Similarly, wild-type (WT) animals, in which the bone morphogenetic protein-mothers against decapentaplegic homolog (Bmp-Smad) pathway is upregulated by iron treatment, fail to suppress hepcidin in response to EPO. To further investigate whether the high level of Bmp-Smad signaling of Tmprss6 KO mice counteracts hepcidin suppression by EPO, we generated double KO Bmp6-Tmprss6 KO mice. Despite having Bmp-Smad signaling and hepcidin levels that are similar to WT mice under basal conditions, double KO mice do not suppress hepcidin in response to EPO. However, pharmacologic downstream inhibition of the Bmp-Smad pathway by dorsomorphin, which targets the BMP receptors, improves the hepcidin responsiveness to EPO in Tmprss6 KO mice. We concluded that the function of matriptase-2 is dominant over that of ERFE and is essential in facilitating hepcidin suppression by attenuating the

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Erythropoietin stimulation decreases hepcidin expression through hematopoietic activity on bone marrow cells in mice

Cited by 47 publications

References 29 publications

A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis

A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis

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

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

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