Limits...
Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia.

Fernandes JC, Garrido P, Ribeiro S, Rocha-Pereira P, Bronze-da-Rocha E, Belo L, Costa E, Reis F, Santos-Silva A - Biomed Res Int (2014)

Bottom Line: Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function.Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia.These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, . 3000-548 Coimbra, Portugal ; Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal.

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.

Show MeSH

Related in: MedlinePlus

Model proposed for erythropoiesis and iron metabolism in erythroid antibody-mediated hypoplasia. Anti-rHuEPO antibodies inhibit both rHuEPO and endogenous EPO leading to anemia that is further aggravated by increased iron that favours hepcidin expression.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4281449&req=5

fig6: Model proposed for erythropoiesis and iron metabolism in erythroid antibody-mediated hypoplasia. Anti-rHuEPO antibodies inhibit both rHuEPO and endogenous EPO leading to anemia that is further aggravated by increased iron that favours hepcidin expression.

Mentions: In the liver, diferric transferrin competes with TfR for binding to Hfe, and, when iron is increased, more Hfe is available to bind to TfR2; this complex, TfR2-Hfe, promotes HJV binding to BMP6, increasing hepcidin synthesis [34, 36]. Indeed, we found that increased serum iron in the 200 IU rHuEPO group was associated with an overexpression of Tf, TfR2, BMP6, Hfe, and HJV in the liver and, accordingly, with an overexpression of Hamp. Moreover, a downregulation in matriptase mRNA was observed in the liver that might further contribute to the overexpression of hepcidin (Figure 6). In accordance with the overexpression of hepcidin, a reduction in serum iron would be expected, due to the degradation of ferroportin by hepcidin, instead of the increase that we found. It is known that regulation of iron absorption is mediated by signals reflecting oxygen tension in enterocytes, intracellular iron levels, and systemic iron needs. Enterocyte oxygen tension regulates iron absorption through its effects on the transcription of HIFs and subsequent changes in transcription of DMT1 [39]. Iron exits the enterocyte through the efflux transporter ferroportin 1 (FPN), the only member of the SLC40 family of transporters and the first reported protein that mediates the exit of iron from cells [40]. Actually, we found an overexpression of DMT1 and ferroportin in the duodenum and liver from the 200 IU rHuEPO group, in response to the anemic state. However, as the overexpression of hepcidin compromises iron absorption and mobilization, the observed increase in serum iron might result mainly from the decreased use of iron for the inhibited erythropoiesis.


Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia.

Fernandes JC, Garrido P, Ribeiro S, Rocha-Pereira P, Bronze-da-Rocha E, Belo L, Costa E, Reis F, Santos-Silva A - Biomed Res Int (2014)

Model proposed for erythropoiesis and iron metabolism in erythroid antibody-mediated hypoplasia. Anti-rHuEPO antibodies inhibit both rHuEPO and endogenous EPO leading to anemia that is further aggravated by increased iron that favours hepcidin expression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4281449&req=5

fig6: Model proposed for erythropoiesis and iron metabolism in erythroid antibody-mediated hypoplasia. Anti-rHuEPO antibodies inhibit both rHuEPO and endogenous EPO leading to anemia that is further aggravated by increased iron that favours hepcidin expression.
Mentions: In the liver, diferric transferrin competes with TfR for binding to Hfe, and, when iron is increased, more Hfe is available to bind to TfR2; this complex, TfR2-Hfe, promotes HJV binding to BMP6, increasing hepcidin synthesis [34, 36]. Indeed, we found that increased serum iron in the 200 IU rHuEPO group was associated with an overexpression of Tf, TfR2, BMP6, Hfe, and HJV in the liver and, accordingly, with an overexpression of Hamp. Moreover, a downregulation in matriptase mRNA was observed in the liver that might further contribute to the overexpression of hepcidin (Figure 6). In accordance with the overexpression of hepcidin, a reduction in serum iron would be expected, due to the degradation of ferroportin by hepcidin, instead of the increase that we found. It is known that regulation of iron absorption is mediated by signals reflecting oxygen tension in enterocytes, intracellular iron levels, and systemic iron needs. Enterocyte oxygen tension regulates iron absorption through its effects on the transcription of HIFs and subsequent changes in transcription of DMT1 [39]. Iron exits the enterocyte through the efflux transporter ferroportin 1 (FPN), the only member of the SLC40 family of transporters and the first reported protein that mediates the exit of iron from cells [40]. Actually, we found an overexpression of DMT1 and ferroportin in the duodenum and liver from the 200 IU rHuEPO group, in response to the anemic state. However, as the overexpression of hepcidin compromises iron absorption and mobilization, the observed increase in serum iron might result mainly from the decreased use of iron for the inhibited erythropoiesis.

Bottom Line: Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function.Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia.These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, . 3000-548 Coimbra, Portugal ; Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal.

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.

Show MeSH
Related in: MedlinePlus