Reciprocal regulation between hepcidin and erythropoiesis and its therapeutic application in erythroid disorders

Wang, Caiyi; Zheng, Fang; Zhu, Zesen; Liu, Jing; Chen, Huiyong

doi:10.1016/j.exphem.2017.05.002

Cited by 24 publications

(19 citation statements)

References 69 publications

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“…EPO and other factors secreted by erythroid cells, such as GDF15, have been proposed to inhibit liver hepcidin expression [17,30]. We found that GDF15 was increased in hemodialysis patients (Table 2), and, thus, may contribute to a repressing effect on hepcidin expression, and to explain the inverse association between ESA dose and hepcidin levels that we found.…”

Section: Discussionmentioning

confidence: 50%

“…Hepcidin induces endocytosis and proteolysis of ferroportin on duodenal enterocytes, reducing iron absorption; and on the membrane of macrophages and hepatocytes, reducing the efflux of iron from the major iron stores, for erythropoiesis [16]. Hepatic hepcidin synthesis is up-regulated by inflammation, through interleukin (IL)-6, transferrin saturation, and liver iron levels, while increasing erythropoietin (EPO), erythropoiesis, and hypoxia down-regulate hepcidin synthesis [17]. Some factors secreted by erythroid cells along the erythropoietic process, such as growth differentiation factor 15 (GDF15) and erythroferron, have also been implicated in the suppression of hepcidin expression [17].…”

Section: Introductionmentioning

confidence: 99%

“…Hepatic hepcidin synthesis is up-regulated by inflammation, through interleukin (IL)-6, transferrin saturation, and liver iron levels, while increasing erythropoietin (EPO), erythropoiesis, and hypoxia down-regulate hepcidin synthesis [17]. Some factors secreted by erythroid cells along the erythropoietic process, such as growth differentiation factor 15 (GDF15) and erythroferron, have also been implicated in the suppression of hepcidin expression [17]. Erythropoiesis and inflammation are, therefore, closely linked and are both altered in dialysis patients [10,18].…”

Section: Introductionmentioning

confidence: 99%

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Hepcidin and diabetes are independently related with soluble transferrin receptor levels in chronic dialysis patients

et al. 2019

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Background: Soluble transferrin receptor (sTfR) is a biomarker of erythropoiesis, which is often impaired in dialysis patients. The aim of our study was to evaluate sTfR levels in chronically dialyzed patients and assess potential determinants of its levels. Methods: We performed a cross-sectional study by evaluating 246 end-stage renal disease patients undergoing dialysis and 32 healthy controls. Circulating levels of interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, hepcidin, sTfR, growth differentiation factor 15 (GDF15), and traditional iron metabolism markers were measured, as well as hemogram parameters. Clinical data was obtained from all patients. Results: Compared to controls, patients presented similar values of sTfR, reticulocytes and reticulocyte production index (RPI), and significantly higher levels of IL-6, CRP, ferritin, hepcidin, TNF-α, and GDF15. Iron, transferrin, hemoglobin levels, erythrocyte count, mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC) values were significantly lower in dialysis group. Within patients, sTfR values were higher in diabetic patients and were positively and significantly correlated with reticulocytes and erythrocytes, RPI, and therapeutic doses of erythropoiesis stimulating agents (ESA) and intravenous iron; and inversely and significantly correlated with circulating iron, ferritin, transferrin saturation, hepcidin, MCH, and MCHC. In multiple linear regression analysis, ESA dose, RPI, serum iron, diabetes, and hepcidin levels were independently associated with sTfR levels in dialysis patients and, thus, with erythropoiesis. Conclusion: Our data suggest that, besides RPI and ESA dose, diabetes and hepcidin are closely related to erythropoiesis in dialysis patients. The influence of diabetes on sTfR levels deserves further investigation.

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Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepcidin and diabetes are independently related with soluble transferrin receptor levels in chronic dialysis patients

et al. 2019

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“…During erythropoietic stimulation, such as in conditions associated with anaemia, hypoxia or during erythropoietin (EPO) administration, HAMP expression is decreased, resulting in increased iron availability for erythropoiesis. This effect is thought to result from factors secreted by erythroid precursors (Shenoy et al , ; Wang et al , ). Several potential candidate ‘erythroid factors’ have been identified.…”

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confidence: 99%

GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1‐mediated BMP‐SMAD signalling suppression

et al. 2019

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Hepcidin (HAMP) synthesis is suppressed by erythropoiesis to increase iron availability for red blood cell production. This effect is thought to result from factors secreted by erythroid precursors. Growth differentiation factor 11 (GDF11) expression was recently shown to increase in erythroid cells of b-thalassaemia, and decrease with improvement in anaemia. Whether GDF11 regulates hepatic HAMP production has never been experimentally studied. Here, we explore GDF11 function during erythropoiesistriggered HAMP suppression. Our results confirm that exogenous erythropoietin significantly increases Gdf11 as well as Erfe (erythroferrone) expression, and Gdf11 is also increased, albeit at a lower degree than Erfe, in phlebotomized wild type and b-thalassaemic mice. GDF11 is expressed predominantly in erythroid burst forming unit-and erythroid colony-forming unit-cells during erythropoiesis. Exogeneous GDF11 administration results in HAMP suppression in vivo and in vitro. Furthermore, exogenous GDF11 decreases BMP-SMAD signalling, enhances SMAD ubiquitin regulatory factor 1 (SMURF1) expression and induces ERK1/2 (MAPK3/1) signalling. ERK1/2 signalling activation is required for GDF11 or SMURF1mediated suppression in BMP-SMAD signalling and HAMP expression. This research newly characterizes GDF11 in erythropoiesis-mediated HAMP suppression, in addition to ERFE.

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“…Accordingly, hepcidin and its expression regulators have been studied as targets for potential therapeutic agents. For example, antibodies, agonists, or antagonists of hepcidin, cytokine receptor antibodies and small‐molecules that modify hepcidin expression, are under investigation or in the process of development as novel therapeutics for these iron disorders . Advances in hepcidin‐targeting therapeutic studies and also an updated understanding of how hepcidin plays crucial roles in systemic iron homeostasis have been recently well‐documented elsewhere.…”

Section: Introductionmentioning

confidence: 99%

Hepcidin and its therapeutic potential in neurodegenerative disorders

Qian

2019

Medicinal Research Reviews

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Abnormally high brain iron, resulting from the disrupted expression or function of proteins involved in iron metabolism in the brain, is an initial cause of neuronal death in neuroferritinopathy and aceruloplasminemia, and also plays a causative role in at least some of the other neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich's ataxia. As such, iron is believed to be a novel target for pharmacological intervention in these disorders. Reducing iron toward normal levels or hampering the increases in iron associated with age in the brain is a promising therapeutic strategy for all iron‐related neurodegenerative disorders. Hepcidin is a crucial regulator of iron homeostasis in the brain. Recent studies have suggested that upregulating brain hepcidin levels can significantly reduce brain iron content through the regulation of iron transport protein expression in the blood‐brain barrier and in neurons and astrocytes. In this review, we focus on the discussion of the therapeutic potential of hepcidin in iron‐associated neurodegenerative diseases and also provide a systematic overview of recent research progress on how misregulated brain iron metabolism is involved in the development of multiple neurodegenerative disorders.

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Reciprocal regulation between hepcidin and erythropoiesis and its therapeutic application in erythroid disorders

Cited by 24 publications

References 69 publications

Hepcidin and diabetes are independently related with soluble transferrin receptor levels in chronic dialysis patients

Hepcidin and diabetes are independently related with soluble transferrin receptor levels in chronic dialysis patients

GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1‐mediated BMP‐SMAD signalling suppression

Hepcidin and its therapeutic potential in neurodegenerative disorders

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