ABSTRACT
Iron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2α (HIF2α). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2α protein expression in kidneys of Irp1(-/-) mice, which led to increased erythropoietin (EPO) expression, polycythemia, and concomitant tissue iron deficiency. Increased HIF2α expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1(-/-) mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Gene Deletion , Hypertension, Pulmonary/complications , Iron Regulatory Protein 1/metabolism , Polycythemia/complications , Protein Biosynthesis , Animals , Diet , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelin-1/genetics , Endothelin-1/metabolism , Erythropoietin/blood , Gastrointestinal Hemorrhage/blood , Gastrointestinal Hemorrhage/complications , Gastrointestinal Hemorrhage/pathology , Hematopoiesis, Extramedullary/drug effects , Hypertension, Pulmonary/blood , Hypertension, Pulmonary/pathology , Iron/pharmacology , Iron Regulatory Protein 1/deficiency , Iron Regulatory Protein 2/metabolism , Longevity , Mice , Models, Biological , Nerve Degeneration/blood , Nerve Degeneration/complications , Nerve Degeneration/pathology , Organ Specificity/drug effects , Polycythemia/blood , Polycythemia/pathology , Protein Biosynthesis/drug effects , Transcriptional Activation/drug effects , Transcriptional Activation/geneticsABSTRACT
The iron-regulatory hormone, hepcidin, regulates systemic iron homeostasis by interacting with the iron export protein ferroportin (FPN1) to adjust iron absorption in enterocytes, iron recycling through reticuloendothelial macrophages, and iron release from storage in hepatocytes. We previously demonstrated that FPN1 was highly expressed in erythroblasts, a cell type that consumes most of the serum iron for use in hemoglobin synthesis. Herein, we have demonstrated that FPN1 localizes to the plasma membrane of erythroblasts, and hepcidin treatment leads to decreased expression of FPN1 and a subsequent increase in intracellular iron concentrations in both erythroblast cell lines and primary erythroblasts. Moreover, injection of exogenous hepcidin decreased FPN1 expression in BM erythroblasts in vivo, whereas iron depletion and associated hepcidin reduction led to increased FPN1 expression in erythroblasts. Taken together, hepcidin decreased FPN1 expression and increased intracellular iron availability of erythroblasts. We hypothesize that FPN1 expression in erythroblasts allows fine-tuning of systemic iron utilization to ensure that erythropoiesis is partially suppressed when nonerythropoietic tissues risk developing iron deficiency. Our results may explain why iron deficiency anemia is the most pronounced early manifestation of mammalian iron deficiency.
