Hypoxic regulation of erythropoiesis and iron metabolism
ABSTRACT The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated 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 factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.
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ABSTRACT: Erythroid hypoplasia (EH) is a rare complication associated with recombinant human erythropoietin (rHuEPO) therapies, due to development of anti-rHuEPO antibodies; however, the underlying mechanisms remain poorly clarified. Our aim was to manage a rat model of antibody-mediated EH induced by rHuEPO and study the impact on iron metabolism and erythropoiesis. Wistar rats treated during 9 weeks with a high rHuEPO dose (200 IU) developed EH, as shown by anemia, reduced erythroblasts, reticulocytopenia, and plasmatic anti-rHuEPO antibodies. Serum iron was increased and associated with mRNA overexpression of hepatic hepcidin and other iron regulatory mediators and downregulation of matriptase-2; overexpression of divalent metal transporter 1 and ferroportin was observed in duodenum and liver. Decreased EPO expression was observed in kidney and liver, while EPO receptor was overexpressed in liver. Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function. Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia. This leads to a serum iron increase, which seems to stimulate hepcidin expression despite no evidence of inflammation, thus suggesting iron as the key modulator of hepcidin synthesis. These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.BioMed Research International 12/2014; DOI:10.1155/2014/421304 · 2.71 Impact Factor
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ABSTRACT: A fully parameterized microscale model for lithium ion cells is presented in which the solid and pores (filled by electrolyte) are spatially resolved, and the mass and charge transport equations describing diffusion and migration in each phase are solved separately. Such a model allows: (1) the correlation of structure-scale, non-homogeneous material properties with macroscopic battery performance, and (2) the correlation of geometrical electrode morphology with macroscopic battery performance (electrode design). The micro-model approach discussed here allows for a simpler parameterization as fewer constitutive relations are needed in contrast to the macro-homogenous physical-based approaches. Input parameters were measured experimentally on lithium manganese oxide electrodes and LiPF6 in 3:7 EC:DMC. Verification and validation for the model is also reported.Journal of The Electrochemical Society 01/2012; 159(6):A697. DOI:10.1149/2.096205jes · 2.86 Impact Factor
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ABSTRACT: Hepcidin, an antimicrobial peptide, is considered to be a key homeostatic regulator of iron metabolism. Tibetan pigs are a Chinese indigenous plateau breed with strong disease resistance. It is therefore of interest to look for porcine hepcidin (pHepc) gene expression in Tibetan pigs in order to clarify the involvement of pHepc in interaction of host defenses and iron homeostasis. In this study, the mRNA expressions of pHepc and the immune response-associated factors were determined by real-time PCR in 30-day-old Tibetan pigs and Landrace pigs were chosen as control. The results showed that the expression of pHepc mRNA in most tissues were higher in Tibetan pigs than those of Landrace pigs, which corresponded to the higher serum iron concentration in Tibetan pigs. In addition, compared to Landrace pigs, higher levels of pro-inflammatory cytokines (TNF-α, IL-1α, IL-1β and IFN-γ), pattern recognition receptors (TLR-2, TLR-4, NOD-1 and NOD-2) and chemokines (MCP-1 and IL-8) were detected in Tibetan pigs, which suggested that Tibetan pigs have a strong immunity. The high expression of pHepc may affect the production of immune factors by regulating iron homeostasis, which may partly explain the strong disease resistance of Tibetan pigs.Livestock Science 01/2015; 171:73-77. DOI:10.1016/j.livsci.2014.11.008 · 1.10 Impact Factor