Anemia is prevalent in patients with chronic kidney disease (CKD) and is primarily due to a complex interplay of relative erythropoietin deficiency, shortened red blood cell survival and abnormalities in iron homeostasis. A key feature in many patients with anemia of CKD is the limited iron availability for an efficient erythropoiesis despite adequate body iron stores. It is now well established that excess levels of the iron regulatory hormone hepcidin are responsible for downregulating the functional expression of the cellular iron exporter, ferroportin, thereby resulting in a blockade of iron absorption from the diet and iron retention in reticuloendothelial macrophage stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in patients. We developed a adenine-induced renal failure model in rats that simulates the renal failure and anemia condition in patients. We modified the Yokozawa et al. model by giving a diet supplemented with 0.75% adenine for 3 weeks followed by adenine free normal diet for another 3 weeks. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which has previously been shown to lower hepcidin levels, was able to mobilize iron into the plasma and improve iron-restricted erythropoiesis in adenine-treated rats. The modified adenine model had a higher survival rate than previously reported models, while maintaining irreversible renal failure and anemia. We demonstrated that adenine rats had increased hepatic hepcidin mRNA levels, decreased serum iron concentration, increased spleen iron content, low hemoglobin levels and inappropriately low EPO levels relative to the degree of anemia, typical of the clinical condition in patients with anemia of CKD. LDN-193189 lowered hepatic hepcidin mRNA and mobilized stored iron into plasma in adenine-treated rats. Moreover, the iron was efficiently incorporated into hemoglobin in reticulocytes. However, LDN-193189 alone did not prevent anemia progression in our model. Lowering hepcidin improved iron availability, but did not improve anemia in an adenine-induced kidney disease model in rats. Co-administration of hepcidin lowering agents with erythropoiesis stimulating agents (ESAs) may be useful as a combination therapy to correct iron balance and thereby reduce the ESA dose needed to achieve target hemoglobin levels.

A HEPCIDIN INHIBITOR MOBILIZES IRON FOR INCORPORATION INTO RED BLOOD CELLS IN AN ADENINE-INDUCED KIDNEY DISEASE MODEL IN RATS / V. Vaja ; tutor: M. D. Cappellini ; co-tutor: J. Babitt ; phd school director: M. Clerici. - : . DIPARTIMENTO DI FISIOPATOLOGIA MEDICO-CHIRURGICA E DEI TRAPIANTI, 2013 Feb 12. ((25. ciclo, Anno Accademico 2012. [10.13130/vaja-valentina_phd2013-02-12].

A HEPCIDIN INHIBITOR MOBILIZES IRON FOR INCORPORATION INTO RED BLOOD CELLS IN AN ADENINE-INDUCED KIDNEY DISEASE MODEL IN RATS

V. Vaja
2013-02-12

Abstract

Anemia is prevalent in patients with chronic kidney disease (CKD) and is primarily due to a complex interplay of relative erythropoietin deficiency, shortened red blood cell survival and abnormalities in iron homeostasis. A key feature in many patients with anemia of CKD is the limited iron availability for an efficient erythropoiesis despite adequate body iron stores. It is now well established that excess levels of the iron regulatory hormone hepcidin are responsible for downregulating the functional expression of the cellular iron exporter, ferroportin, thereby resulting in a blockade of iron absorption from the diet and iron retention in reticuloendothelial macrophage stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in patients. We developed a adenine-induced renal failure model in rats that simulates the renal failure and anemia condition in patients. We modified the Yokozawa et al. model by giving a diet supplemented with 0.75% adenine for 3 weeks followed by adenine free normal diet for another 3 weeks. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which has previously been shown to lower hepcidin levels, was able to mobilize iron into the plasma and improve iron-restricted erythropoiesis in adenine-treated rats. The modified adenine model had a higher survival rate than previously reported models, while maintaining irreversible renal failure and anemia. We demonstrated that adenine rats had increased hepatic hepcidin mRNA levels, decreased serum iron concentration, increased spleen iron content, low hemoglobin levels and inappropriately low EPO levels relative to the degree of anemia, typical of the clinical condition in patients with anemia of CKD. LDN-193189 lowered hepatic hepcidin mRNA and mobilized stored iron into plasma in adenine-treated rats. Moreover, the iron was efficiently incorporated into hemoglobin in reticulocytes. However, LDN-193189 alone did not prevent anemia progression in our model. Lowering hepcidin improved iron availability, but did not improve anemia in an adenine-induced kidney disease model in rats. Co-administration of hepcidin lowering agents with erythropoiesis stimulating agents (ESAs) may be useful as a combination therapy to correct iron balance and thereby reduce the ESA dose needed to achieve target hemoglobin levels.
CAPPELLINI, MARIA DOMENICA
CLERICI, MARIO SALVATORE
anemia; chronic kidney disease ; hepcidin
Settore MED/09 - Medicina Interna
A HEPCIDIN INHIBITOR MOBILIZES IRON FOR INCORPORATION INTO RED BLOOD CELLS IN AN ADENINE-INDUCED KIDNEY DISEASE MODEL IN RATS / V. Vaja ; tutor: M. D. Cappellini ; co-tutor: J. Babitt ; phd school director: M. Clerici. - : . DIPARTIMENTO DI FISIOPATOLOGIA MEDICO-CHIRURGICA E DEI TRAPIANTI, 2013 Feb 12. ((25. ciclo, Anno Accademico 2012. [10.13130/vaja-valentina_phd2013-02-12].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/217464
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