Iron as the Key Modulator of Hepcidin Expression in Erythroid Antibody-Mediated Hypoplasia

Fernandes, João; Garrido, Patrícia; Ribeiro, Sandra; Rocha‐Pereira, Petronila; Bronze-da-Rocha, Elsa; Belo, Luı́s; Costa, Elı́sio; Reis, Flávio; Santos-Silva, Alice

doi:10.1155/2014/421304

Cited by 7 publications

(6 citation statements)

References 49 publications

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“…It is reported that in both healthy, non-diseased (with normal hemoglobin) mice ( Gammella et al., 2015 ) and humans ( Robach et al., 2009 ; Ashby et al., 2010 ), hepcidin is down-regulated by rhEPO. On the other hand, high dose erythropoietin treatment induced EPO resistance in anemic rats, which is associated with anti-rHuEPO antibodies and higher hepcidin expression ( Fernandes et al., 2014 ). Also, clinically a significant positive relation between hepcidin and erythropoietin resistance is observed in anemic patients ( Petrulien ė et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state

Joharapurkar

Patel

Kshirsagar

et al. 2022

Current Research in Pharmacology and Drug Discovery

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Section: Discussionmentioning

confidence: 99%

Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state

Joharapurkar

Patel

Kshirsagar

et al. 2022

Current Research in Pharmacology and Drug Discovery

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“…Previous studies have shown that iron overload can up-regulate hepcidin expression, and iron deficiency can down-regulate its expression, which is an important negative feedback mechanism for iron homeostasis in the body [ 27 , 28 ]. Recent studies have provided further evidence that iron is the key regulator of hepcidin gene expression via the BMP6/SMAD signaling pathway in hepatocytes [ 14 , 29 , 30 ]. Accordingly, we observed a significant increase in SI levels ( Fig 2A ) and liver hepcidin gene overexpression ( Fig 4A ) compared with observations in the control rats.…”

Section: Discussionmentioning

confidence: 99%

Change in iron metabolism in rats after renal ischemia/reperfusion injury

et al. 2017

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Previous studies have indicated that hepcidin, which can regulate iron efflux by binding to ferroportin-1 (FPN1) and inducing its internalization and degradation, acts as the critical factor in the regulation of iron metabolism. However, it is unknown whether hepcidin is involved in acute renal ischemia/reperfusion injury (IRI). In this study, an IRI rat model was established via right renal excision and blood interruption for 45 min in the left kidney, and iron metabolism indexes were examined to investigate the change in iron metabolism and to analyze the role of hepcidin during IRI. From 1 to 24 h after renal reperfusion, serum creatinine and blood urea nitrogen were found to be time-dependently increased with different degrees of kidney injury. Regular variations in iron metabolism indexes in the blood and kidneys were observed in renal IRI. Renal iron content, serum iron and serum ferritin increased early after reperfusion and then declined. Hepcidin expression in the liver significantly increased early after reperfusion, and its serum concentration increased beginning at 8 h after reperfusion. The splenic iron content decreased significantly in the early stage after reperfusion and then increased time-dependently with increasing reperfusion time, and the hepatic iron content showed a decrease in the early stage after reperfusion. The early decrease of the splenic iron content and hepatic iron content might indicate their contribution to the increase in serum iron in renal IRI. In addition, the duodenal iron content showed time-dependently decreased since 12 h after reperfusion in the IRI groups compared to the control group. Along with the spleen, the duodenum might contribute to the decrease in serum iron in the later stage after reperfusion. The changes in iron metabolism indexes observed in our study demonstrate an iron metabolism disorder in renal IRI, and hepcidin might be involved in maintaining iron homeostasis in renal IRI. These findings might suggest a self-protection mechanism regulating iron homeostasis in IRI and provide a new perspective on iron metabolism in attenuating renal IRI.

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“…This study intended to evaluate the effects of rHuEPO therapy in doses commonly used to correct anemia in CKD patients (100 and 200 IU/kg BW week) and in higher doses used in hyporesponsive CKD patients (400 and 600 IU/kg BW/week). A 3‐week period of treatment was selected in order to avoid the development of anti‐rHuEPO antibodies, as previously described by us .…”

Section: Discussionmentioning

confidence: 99%

SP313LIVER IRON IS A MAJOR REGULATOR OF HEPCIDIN GENE EXPRESSION VIA BMP/SMAD PATHWAY IN A RAT MODEL OF CHRONIC RENAL FAILURE UNDER TREATMENT WITH HIGH rHuEPO DOSES

Ribeiro

Garrido

Fernandes

et al. 2016

Nephrology Dialysis Transplantation

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Introduction and Aims: Hepcidin is the major central regulator of iron metabolism, controlling iron absorption and mobilization. Considering its interaction with several factors that are altered in chronic kidney disease (CKD), particularly in hyporesponsive CKD patients under therapy with high recombinant human erythropoietin (rHuEPO) doses, we aimed to study the impact of increasing rHuEPO doses on the regulation of iron-hepcidin metabolism. Methods: Male Wistar rats, 12 weeks old, were divided in 6 groups: CRF (induced by a two-stage 5/6 nephrectomy), CRF-rHuEPO treated (100, 200, 400 and 600IU/Kg body weight/week) during 3 weeks and Sham-operated (surgery without kidney mass reduction). Hematological and iron data were evaluated, as well as, the expression of several genes involving iron metabolism and the quantification of some proteins by western blot. Mann-Whitney test was used to evaluate differences between groups. Results: We found that the rHuEPO stimulus triggers a first wave to achieve correction of anemia, by inhibiting hepcidin synthesis, favoring erythropoiesis and iron absorption; this continuous enhanced iron absorption lead to iron overload, as showed by the hepatic iron deposits found in rats treated with higher rHuEPO dose that seems to trigger the up-regulation of hepcidin synthesis through the activation of the BMP6/SMAD pathway. Conclusions: Our data suggests that liver iron overload is an important stimuli for hepcidin synthesis, stronger than the inhibitory effect of high rHuEPO doses; moreover, our findings raise the hypothesis that when high inflammation (triggering hepcidin expression) is associated with increased iron stores in hemodialysis patients, hepcidin expression is also up-regulated via BMP6, enhancing hepcidin synthesis, leading, therefore, to worsening of anemia and, eventually, to a hyporesponse/resistance to rHuEPO therapy.

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Iron as the Key Modulator of Hepcidin Expression in Erythroid Antibody-Mediated Hypoplasia

Cited by 7 publications

References 49 publications

Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state

Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state

Change in iron metabolism in rats after renal ischemia/reperfusion injury

SP313LIVER IRON IS A MAJOR REGULATOR OF HEPCIDIN GENE EXPRESSION VIA BMP/SMAD PATHWAY IN A RAT MODEL OF CHRONIC RENAL FAILURE UNDER TREATMENT WITH HIGH rHuEPO DOSES

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