Hepcidin Is Involved in Iron Regulation in the Ischemic Brain

Ding, Hui; Yan, Cai-Zhen; Shi, Honglian; Zhao, Ya-Shuo; Chang, Shiyang; Yu, Peng; Wu, Wenshuang; Zhao, Chenyang; Chang, Yan‐Zhong; Duan, Xingguang

doi:10.1371/journal.pone.0025324

Cited by 131 publications

(114 citation statements)

References 51 publications

(69 reference statements)

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“…Influence on T2 * -w signal intensity by accumulation of myelin and calcium has also been described [4] . However, increased levels of iron after stroke [5][6][7][8][9] and the pathological correlation between T2 * -w hypointensities and iron deposits [10,19,32,33] have been described extensively whereas myelin accumulation is not a wellknown consequence of stroke. In addition, none of the patients with available CT showed calcifications in the thalamus or basal ganglia; so, we think it is unlikely that the measured hypointensities are due to calcium accumulation.…”

Section: Discussionmentioning

confidence: 99%

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MRI Susceptibility Changes Suggestive of Iron Deposition in the Thalamus after Ischemic Stroke

Etten¹,

Dumas²,

Bogaard³

et al. 2015

Cerebrovasc Dis

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Background: Iron accumulation has been linked to neuronal injury following cerebral ischemia. In animals, a hypointense signal on T2*-weighted (T2*-w) MRI correlated with iron deposits in remote brain regions following ischemic stroke. We aim to assess whether such signal changes are present in remote brain structures following ischemic stroke in humans. Methods: We analyzed T2*-w images of 36 patients with unilateral ischemic stroke and 36 healthy controls. Regions of interest (ROIs) consisted of the thalamus, putamen, globus pallidus, caudate nucleus and white matter. To quantify signal intensity in ROIs ipsilateral to the infarct, signal intensity was measured in the ROIs in both hemispheres and a ratio of signal intensity was calculated. Signal asymmetry was compared between patients and controls and its relation with time after stroke onset was assessed. Results: In 34 (94%) patients, the thalamus ipsilateral to the infarct was hypointense compared to the contralateral thalamus. Ipsilateral thalamic signal hypointensity was significantly different between patients and controls (p < 0.001) and was present as early as 1 day after stroke onset. In other ROIs, no difference was found between patients and controls. No association was found between intensity asymmetry and time. Conclusion: We demonstrated that, as early as days after ischemic stroke, T2*-w signal intensity was decreased in the ipsilateral thalamus. This finding might indicate pathophysiologic changes in regions outside the infarcted area, possibly reflecting toxic iron accumulation.

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Section: Discussionmentioning

confidence: 99%

“…Excessive free iron increases the vulnerability to oxidative stress leading to additional neurotoxicity after cerebral damage [1][2][3][4] . Increased levels of free iron and ferritin, a protein that stores iron, have been found after cerebral ischemia [5][6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

MRI Susceptibility Changes Suggestive of Iron Deposition in the Thalamus after Ischemic Stroke

Etten¹,

Dumas²,

Bogaard³

et al. 2015

Cerebrovasc Dis

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“…12,25,26 As in the periphery, Fpn1 is the sole known cellular iron exporter and plays a key role in brain iron release. 22,46 The turnover of Fpn1 is controlled by hepcidin. Injection of hepcidin into the lateral cerebral ventricle resulted in decreased Fpn1 protein content in the cerebral cortex, the hippocampus, and the striatum.…”

Section: Figmentioning

confidence: 99%

“…Injection of hepcidin into the lateral cerebral ventricle resulted in decreased Fpn1 protein content in the cerebral cortex, the hippocampus, and the striatum. 46 Functionally, hepcidin acts to internalize Fpn1, leading to its degradation and thereby blocking iron release from cells into extracellular fluid. Thus, facilitation of iron efflux by hepcidin-Fpn pathway would be able to protect cells from excessive accumulation of iron.…”

Section: Figmentioning

confidence: 99%

Calorie Restriction Down-Regulates Expression of the Iron Regulatory Hormone Hepcidin in Normal and d-Galactose–Induced Aging Mouse Brain

Wei

Shi²,

Li³

et al. 2014

Rejuvenation Research

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It has been shown that iron progressively accumulates in the brain with age. Calorie restriction (CR) may allay many of the adverse effects of aging on the brain, yet the underlying mechanisms, in particular in relation to brain iron metabolism, remain unclear. This study aimed to investigate the role of CR in the regulation of cerebral cellular iron homeostasis. C57BL/6 mice were randomly divided into four groups of eight. The control group was fed a conventional diet ad libitum; the CR group received 70% of the calories of the control mouse intake per day; the d-galactose (d-gal) group received subcutaneous injection of d-gal at a dose of 100 mg/kg once daily to produce mouse model of aging; the d-gal plus CR group received both of the two interventions for 14 weeks. The Morris water maze (MWM) was employed to test the cognitive performance of all animals, and the expression of iron regulatory genes, ferroportin and hepcidin, in the cortex and hippocampus were detected by quantitative real-time PCR. Compared to the controls, the d-gal group mice showed significant spatial reference memory deficits in the MWM test, whereas the d-gal-CR group mice exhibited almost normal cognitive function, indicating that CR protects against d-gal-induced learning and memory impairment. Hepcidin mRNA expression was increased in the d-gal group, decreased in the CR group, and was basically unchanged in the d-gal-CR group. There was no statistical difference in the transmembrane iron exporter ferroportin expression between control and any of the experimental groups. The results suggest that the antiaging effects of CR might partially lie in its capacity to reduce or avoid age-related iron accumulation in the brain through down-regulating expression of brain hepcidin-the key negative regulator for intracellular iron efflux-and that facilitating the balance of brain iron metabolism may be a promising anti-aging measure.

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“…21 HIF also regulates hepcidin and can thereby affect iron homeostasis. 22,23 Elevated hepcidin levels limit iron absorption in the gut, 24 limiting iron available for erythropoiesis and exacerbating anemia. 25 Concordantly, 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.…”

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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

171

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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Hepcidin Is Involved in Iron Regulation in the Ischemic Brain

Cited by 131 publications

References 51 publications

MRI Susceptibility Changes Suggestive of Iron Deposition in the Thalamus after Ischemic Stroke

MRI Susceptibility Changes Suggestive of Iron Deposition in the Thalamus after Ischemic Stroke

Calorie Restriction Down-Regulates Expression of the Iron Regulatory Hormone Hepcidin in Normal and d-Galactose–Induced Aging Mouse Brain

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

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