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.
- SourceAvailable from: James Stangoulis
Critical reviews in food science and nutrition 07/2015; DOI:10.1080/10408398.2015.1050483 · 5.55 Impact Factor
- "Recently, it was shown that NF-κB (nuclear factor κB) is a modulator of HIF 2 expression in the presence of normal oxygen pressure (Haase et al., 2010, Willam, 2014). NF-κB indirectly controls HIF 2α through its control of HIF 1β (van Uden et al., 2011). "
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- "Hepatic EPO contributes about 10% of the plasma EPO in adults. Hypoxia is the primary physiological stimulus for EPO production, which, depending on the hypoxic condition increases serum EPO levels up to several hundred-fold (Haase, 2010; Jelkmann, 2011). As already mentioned, animal studies have shown than the main regulator of hepatic EPO production is HIF-2␣ and not HIF- 1␣ (Scortegagna et al., 2005; Rankin et al., 2007; Kapitsinou et al., 2010). "
ABSTRACT: Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate the cellular response to low oxygen. Although HIF-1 is usually considered as the principal mediator of hypoxic adaptation, several tissues and different cell types express both HIF-1 and HIF-2 isoforms under hypoxia or when treated with hypoxia mimetic chemicals such as cobalt. However, the similarities or differences between HIF-1 and HIF-2, in terms of their tissue- and inducer-specific activation and function, are not adequately characterized. To address this issue, we investigated the effects of true hypoxia and hypoxia mimetics on HIF-1 and HIF-2 induction and specific gene transcriptional activity in two hepatic cancer cell lines, Huh7 and HepG2. Both hypoxia and cobalt caused rapid induction of both HIF-1α and HIF-2α proteins. Hypoxia induced erythropoietin (EPO) expression and secretion in a HIF-2-dependent way. Surprisingly, however, EPO expression was not induced when cells were treated with cobalt. In agreement, both HIF-1- and HIF-2-dependent promoters (of PGK and SOD2 genes, respectively) were activated by hypoxia while cobalt only activated the HIF-1-dependent PGK promoter. Unlike cobalt, other hypoxia mimetics such as DFO and DMOG activated both types of promoters. Furthermore, cobalt impaired the hypoxic stimulation of HIF-2, but not HIF-1, activity and cobalt-induced HIF-2α interacted poorly with USF-2, a HIF-2-specific co-activator. These data show that, despite similar induction of HIF-1α and HIF-2α protein expression, HIF-1 and HIF-2 specific gene activating functions respond differently to different stimuli and suggest the operation of oxygen-independent and gene- or tissue-specific regulatory mechanisms involving additional transcription factors or co-activators.The international journal of biochemistry & cell biology 08/2013; 45(11). DOI:10.1016/j.biocel.2013.07.025 · 4.24 Impact Factor
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- "However, the roles of HIF-1 and HIF-2 in the adaptation to hypoxia are quite distinct . Thus, HIF-1 orchestrates an increase in glucose metabolism  and cell cycle arrest , while HIF-2 activates cancer cell proliferation  , erythropoiesis and iron metabolism . Therefore, a balance between HIF-1 and HIF-2 pathways may become a determinative factor in cell fate under energy crisis conditions. "
ABSTRACT: Background: Along with other regulators of cell metabolism, hypoxia-inducible factors HIF-1 and HIF-2 differ-entially regulate cell adaptation to hypoxia. Switches in HIF-1/HIF-2 signaling in chronic hypoxia have not been fully investigated. Methods: Proliferation, viability, apoptosis, neuronal and bioenergetic markers, mitochondrial function, respi-ration, glycolysis, HIF signalling, responses to O 2 and glucose deprivation (OGD) were examined using tumor PC12 and SH-SY5Y cells continuously grown at 3% O 2 . Results: Hypoxic PC12 cells (H-cells) exhibit reduced proliferation and histone H4 acetylation, NGF-independent differentiation, activation of AMPK, inhibition of Akt, altered mitochondria and response to NGF. Cellular cytochrome c is increased with no effect on apoptosis. Reduction in respiration has minor effect on cellular ATP which is maintained through activated uptake (GLUT1) and utilization (HK2, PFK2) of glu-cose. H-cells exhibit resistance to OGD linked to increased glycogen stores. HIF-2alpha protein is decreased without changes in mRNA. Unlike HIF-1alpha, HIF-2alpha is not stabilized pharmacologically or by O 2 depri-vation. Capacity for HIF-2alpha stabilization is partly restored when H-cells are cultured at normoxia. In low-respiring SH-SY5Y cells cultured under the same conditions HIF-2alpha stabilization and energy budget are not affected. Conclusions: In chronically hypoxic PC12 cells glycolytic energy budget, increased energy preservation and low susceptibility to OGD are observed. HIF-2alpha no longer orchestrates adaptive responses to anoxia. General significance: Demonstrated switch in HIF-1/HIF-2 signaling upon chronic hypoxia can facilitate cell survival in energy crisis, by regulating balance between energy saving and decrease in proliferation, on one hand and active cell growth and tumor expansion, on the other.Biochimica et Biophysica Acta (BBA) - General Subjects 02/2013; 1830(6):3553. DOI:10.1016/j.bbagen.2013.02.016 · 3.83 Impact Factor