Effect of Erythropoietin on the Expression of Murine Transferrin Receptor 2

Berezovsky, B. S.; Báječný, Martin; Frýdlová, Jana; Gurieva, Iuliia; Rogalsky, Daniel W.; Přikryl, Petr; Pospíšil, Vít; Nečas, E; Vokurka, Martin; Krijt, Jan

doi:10.3390/ijms22158209

Cited by 4 publications

(5 citation statements)

References 44 publications

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“…Additionally, the well‐established action of SGLT2 inhibitors to mute inflammation in the heart and bone marrow 92–94 (also the result of enhanced SIRT1 signalling 93–95 ) might contribute to the observed decline in both hepcidin and ferritin. Finally, increased erythropoietin activity upregulates TfR1 and reduces transferrin saturation, ferritin and hepcidin 96–98 . Importantly, if cytosolic Fe 2+ levels were to rise excessively, SIRT1 can prevent the deleterious consequences of iron overload by its action to suppress ferroptosis 99,100 …”

Section: Effect Of Sodium–glucose Cotransporter 2 Inhibitors On Iron ...mentioning

confidence: 99%

“…Finally, increased erythropoietin activity upregulates TfR1 and reduces transferrin saturation, ferritin and hepcidin. 96 , 97 , 98 Importantly, if cytosolic Fe 2+ levels were to rise excessively, SIRT1 can prevent the deleterious consequences of iron overload by its action to suppress ferroptosis. 99 , 100 …”

Section: Effect Of Sodium–glucose Cotransporter 2 Inhibitors On Iron ...mentioning

confidence: 99%

“…Finally, increased erythropoietin activity upregulates TfR1 and reduces transferrin saturation, ferritin and hepcidin. [96][97][98] Importantly, if cytosolic Fe 2+ levels were to rise excessively, SIRT1 can prevent the deleterious consequences of iron overload by its action to suppress ferroptosis. 99,100 Therefore, through their effect to enhance nutrient deprivation signalling and suppress inflammation, SGLT2 inhibitors act to increase in bioreactive cytosolic Fe 2+ together with an increase in erythropoietin, thus stimulating erythroid precursors and haemoglobin synthesis to produce an increase in red blood cell mass.…”

Section: Mechanistic Implications Of Changes In Iron Homeostasis Duri...mentioning

confidence: 99%

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How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

Packer

2022

European J of Heart Fail

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Many patients with heart failure have an iron‐deficient state, which can limit erythropoiesis in erythroid precursors and ATP production in cardiomyocytes. Yet, treatment with sodium–glucose cotransporter 2 (SGLT2) inhibitors produces consistent increases in haemoglobin and haematocrit, even in patients who are iron‐deficient before treatment, and this effect remains unattenuated throughout treatment even though SGLT2 inhibitors further aggravate biomarkers of iron deficiency. Heart failure is often accompanied by systemic inflammation, which activates hepcidin, thus impairing the duodenal absorption of iron and the release of iron from macrophages and hepatocytes, leading to a decline in circulating iron. Inflammation and oxidative stress also promote the synthesis of ferritin and suppress ferritinophagy, thus impairing the release of intracellular iron stores and leading to the depletion of bioreactive cytosolic Fe2+. By alleviating inflammation and oxidative stress, SGLT2 inhibitors down‐regulate hepcidin, upregulate transferrin receptor protein 1 and reduce ferritin; the net result is to increase the levels of cytosolic Fe2+ available to mitochondria, thus enabling the synthesis of heme (in erythroid precursors) and ATP (in cardiomyocytes). The finding that SGLT2 inhibitors can induce erythrocytosis without iron supplementation suggests that the abnormalities in iron diagnostic tests in patients with mild‐to‐moderate heart failure are likely to be functional, rather than absolute, that is, they are related to inflammation‐mediated trapping of iron by hepcidin and ferritin, which is reversed by treatment with SGLT2 inhibitors. An increase in bioreactive cytosolic Fe2+ is also likely to augment mitochondrial production of ATP in cardiomyocytes, thus retarding the progression of heart failure. These effects on iron metabolism are consistent with (i) proteomics analyses of placebo‐controlled trials, which have shown that biomarkers of iron homeostasis represent the most consistent effect of SGLT2 inhibitors; and (ii) statistical mediation analyses, which have reported striking parallelism of the effect of SGLT2 inhibitors to promote erythrocytosis and reduce heart failure events.

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Section: Effect Of Sodium–glucose Cotransporter 2 Inhibitors On Iron ...mentioning

confidence: 99%

Section: Effect Of Sodium–glucose Cotransporter 2 Inhibitors On Iron ...mentioning

confidence: 99%

Section: Mechanistic Implications Of Changes In Iron Homeostasis Duri...mentioning

confidence: 99%

See 1 more Smart Citation

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

Packer

2022

European J of Heart Fail

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“…Mutations of the erythroferrone gene (ERFE A260S) have been found in congenital dyserythropoietic anemia type II patients (12.5%), wherein ineffective erythropoiesis can lead to increased ERFE production, decreased hepcidin secretion, and ultimately iron loading [ 22 ]. A recent study in mice has shown that a single dose of EPO increased the expression and production of ERFE in the erythroblast of Fam132b, transferrin receptor-1 (TfR1), and -2 (TfR2) in the spleen while decreasing hepatic hepcidin mRNA expression [ 23 ]. Nevertheless, serum levels of ERFE and EPO, along with erythropoietic activity and hepcidin, were higher in active rheumatoid arthritis patients who had anemia than in control patients.…”

Section: Discussionmentioning

confidence: 99%

Effect of Recombinant Human Erythroferrone Protein on Hepcidin Gene (Hamp1) Expression in HepG2 and HuH7 Cells

et al. 2021

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Iron is essential for all living organisms. It is strictly controlled by iron transporters, transferrin receptors, ferroportin and hepcidin. Erythroferrone (ERFE) is an iron-regulatory hormone which is highly expressed in erythroblasts by erythropoietin (EPO) stimulation and osteoblasts independently of EPO by sequestering bone morphogenetic proteins and inhibiting hepatic hepcidin expression. Although the hepcidin suppressive function of ERFE is known, its receptors still require investigation. Here, we aim to identify ERFE receptors on the HepG2 and Huh7 cells responsible for ERFE. Recombinant ERFE (rERFE) was first produced in HEK293 cells transfected with pcDNA3.1 + ERFE, then purified and detected by Western blot. The liver cells were treated with an rERFE-rich medium of transfected HEK293 cells and a purified rERFE-supplemented medium at various time points, and hepcidin gene (Hamp1) expression was determined using qRT-PCR. The results show that 37-kD rERFE was expressed in HEK293 cells. Hamp1 was suppressed at 3 h and 6 h in Huh7 cells after rERFE treatments (p < 0.05), then restored to the original levels. Hamp1 was activated after treatment with purified rERFE for 24 h and 48 h. Together, these results reveal that ERFE suppressed Hamp1 expression in liver cells, possibly acting on membrane ERFE receptor, which in Huh7 cells was more sensitive to the ERFE concentrate.

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“…Other papers studied the regulation of erythropoiesis. Berezovsky et al [ 11 ] were interested in the mechanism by which Erythropoietin (EPO) downregulates hepcidin expression via the erythroferrone (ERFE) secreted by erythroblasts expressing transferrin receptor 2 (TFR2). They found that, after the administration of a single dose of EPO, splenic ERFE expression increased at 4 h while liver hepcidin mRNA decreased at 16 h. Additionally, splenic TFR2 and TFR1 proteins increased after EPO treatment.…”

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confidence: 99%