Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors and Iron Metabolism

Abstract

The production of erythropoietin (EPO), the main regulator of erythroid differentiation, is regulated by hypoxia-inducible factor (HIF). HIF2α seems to be the principal regulator of EPO transcription, but HIF1α and 3α also may have additional influences on erythroid maturation. HIF is also involved in the regulation of iron, an essential component in erythropoiesis. Iron is essential for the organism but is also highly toxic, so its absorption and retention are strictly controlled. HIF also induces the synthesis of proteins involved in iron regulation, thereby ensuring the availability of iron necessary for hematopoiesis. Iron is a major component of hemoglobin and is also involved in erythrocyte differentiation and proliferation and in the regulation of HIF. Renal anemia is a condition in which there is a lack of stimulation of EPO synthesis due to decreased HIF expression. HIF prolyl hydroxylase inhibitors (HIF-PHIs) stabilize HIF and thereby allow it to be potent under normoxic conditions. Therefore, unlike erythropoiesis-stimulating agents, HIF-PHI may enhance iron absorption from the intestinal tract and iron supply from reticuloendothelial macrophages and hepatocytes into the plasma, thus facilitating the availability of iron for hematopoiesis. The only HIF-PHI currently on the market worldwide is roxadustat, but in Japan, five products are available. Clinical studies to date in Japan have also shown that HIF-PHIs not only promote hematopoiesis, but also decrease hepcidin, the main regulator of iron metabolism, and increase the total iron-binding capacity (TIBC), which indicates the iron transport capacity. However, concerns about the systemic effects of HIF-PHIs have not been completely dispelled, warranting further careful monitoring.