Defective regulation of iron transporters leading to iron excess in the polymorphonuclear leukocytes of patients on maintenance hemodialysis

Abstract

Background: Although hemodialysis (HD) patients are suspected of having defectively regulated iron metabolism, intracellular iron status has never been investigated thoroughly. To clarify the iron metabolism of HD patients, proteins involved in iron import (transferrin receptor [TfR]), as well as export (ferroportin 1), were investigated in polymorphonuclear leukocytes (PMNLs). Relations between iron status and several PMNL functions also were tested. Methods: Seventeen HD patients and 17 controls were recruited. Relative quantitative polymerase chain reaction was used to measure ferroportin 1 and TfR messenger RNA (mRNA), and ferroportin 1 and TfR expression were semiquantified by means of Western blot analysis or immunohistochemistry. PMNL functions also were examined. Results: Serum iron levels were significantly lower in HD patients than controls, and serum ferritin levels, as well as PMNL ferritin and iron content, were elevated in HD patients. Ferroportin 1 mRNA levels were substantially lower in PMNLs from HD patients, whereas TfR mRNA levels were higher. Western blot analysis and immunohistochemistry confirmed that expression of the corresponding proteins paralleled those of the mRNAs. PMNL phagocytic and bactericidal activity did not differ between HD patients and controls. Chemotactic peptide f-Met-Leu-Phe-stimulated degranulation activity of lactoferrin (Lf) was decreased significantly in HD patients, whereas those of myeloperoxidase and elastase were accelerated. Lf release correlated negatively with intracellular ferritin level. Conclusion: We show for the first time that increased iron levels in PMNLs of HD patients were associated with downregulation of ferroportin 1 and upregulation of TfR, which might be linked to hypercytokinemia.