Reduction of a marker of oxidative stress with enhancement of iron utilization by erythropoiesis activation following epoetin beta pegol administration in iron-loaded db/db mice

Iron, an essential element for various biological processes, can induce oxidative stress. We hypothesized that iron utilization for erythropoiesis, stimulated by epoetin beta pegol (C.E.R.A.), a long-acting erythropoiesis-stimulating agent, contributes to the reduction of iron-induced oxidative stress. We first investigated the sensitivity of several biomarkers to detect oxidative stress in mice by altering the amount of total body iron; we then investigated whether C.E.R.A. ameliorated oxidative stress through enhanced iron utilization. We treated db/db mice with intravenous iron-dextran and evaluated several biomarkers of iron-induced oxidative stress. In mice loaded with 5 mg/head iron, hepatic iron content was elevated and the oxidative stress marker d-ROMs (serum derivatives of reactive oxygen metabolites) was increased, whereas urinary 8-hydroxy-2′-deoxyguanosine and serum malondialdehyde were not, indicating that d-ROMs is a sensitive marker of iron-induced oxidative stress. To investigate whether C.E.R.A. ameliorated oxidative stress, db/db mice were intravenously administered iron-dextran or dextran only, followed by C.E.R.A. Hemoglobin level increased, while hepatic iron content decreased after C.E.R.A. treatment. Serum d-ROMs decreased after C.E.R.A. treatment in the iron-dextran-treated group. Our results suggest that C.E.R.A. promotes iron utilization for erythropoiesis through mobilization of hepatic iron storage, leading to a decrease in serum oxidative stress markers in iron-loaded db/db mice.