IRP1 Regulation of Erythropoietin (EPO) Production. The production of EPO in renal interstitial fibroblasts is shown for normal individuals under iron-replete conditions, and for normal and IRP1 knockout individuals under iron-deficient conditions. Under iron-replete conditions (left panel), IRP1 contains an iron-sulfur cluster and has cytoplasmic aconitase activity, but it does not bind the iron responsive element (IRE) of HIF2α. Under conditions of iron deficiency, IRP1 lacks the iron-sulfur cluster, and in this state, binds the IRE of HIF2α mRNA (center panel). HIF2α is a component of the transcription factor complex that controls EPO production. Relative amounts of HIF2α (pink), hydroxylated HIF2α (white), and EPO (red) are indicated by the size of rectangles. In iron-deficient individuals (center panel), IRP1 binding to the 5’ IRE of HIF2α mRNA inhibits translation, thereby reducing the availability of HIF2α, ultimately restricting EPO production by renal interstitial cells and thereby contributing to the anemia of iron deficiency. When oxygen delivery to the kidneys is normal, HIF2α is rapidly hydroxylated by iron-containing prolyl-hydroxyase (blue ovals) and undergoes proteasomal degradation so that renal HIF2α is low and only a few cells produce EPO under either iron-replete (left panel) or iron-deficient (middle panel) conditions. Under conditions of renal hypoxia, as occurs with anemia, less oxygen is available to support the prolyl-hydroxylation reaction. Consequently, degradation of HIF2α is limited, resulting in increased renal HIF2α and greater production of EPO compared with renal normoxia. This process contributes to the increase in EPO production that is observed in response to anemia. In normal individuals with intact IRP1 function, iron deficiency reduces the amount of HIF2α formed and, therefore, restricts the amount of EPO produced, even under hypoxic conditions (middle panel). Therefore, renal HIF2α and EPO production are decreased in iron deficiency as compared with iron-replete conditions. In the IRP1 knockout condition (right panel), basal HIF2α and EPO production are increased under normal conditions, and iron deficiency exacerbates these already elevated levels, presumably by decreasing the activity of iron-containing prolyl-hydroxyase (smaller blue oval), even when the kidney is normoxic.

IRP1 Regulation of Erythropoietin (EPO) Production. The production of EPO in renal interstitial fibroblasts is shown for normal individuals under iron-replete conditions, and for normal and IRP1 knockout individuals under iron-deficient conditions. Under iron-replete conditions (left panel), IRP1 contains an iron-sulfur cluster and has cytoplasmic aconitase activity, but it does not bind the iron responsive element (IRE) of HIF2α. Under conditions of iron deficiency, IRP1 lacks the iron-sulfur cluster, and in this state, binds the IRE of HIF2α mRNA (center panel). HIF2α is a component of the transcription factor complex that controls EPO production. Relative amounts of HIF2α (pink), hydroxylated HIF2α (white), and EPO (red) are indicated by the size of rectangles. In iron-deficient individuals (center panel), IRP1 binding to the 5’ IRE of HIF2α mRNA inhibits translation, thereby reducing the availability of HIF2α, ultimately restricting EPO production by renal interstitial cells and thereby contributing to the anemia of iron deficiency. When oxygen delivery to the kidneys is normal, HIF2α is rapidly hydroxylated by iron-containing prolyl-hydroxyase (blue ovals) and undergoes proteasomal degradation so that renal HIF2α is low and only a few cells produce EPO under either iron-replete (left panel) or iron-deficient (middle panel) conditions. Under conditions of renal hypoxia, as occurs with anemia, less oxygen is available to support the prolyl-hydroxylation reaction. Consequently, degradation of HIF2α is limited, resulting in increased renal HIF2α and greater production of EPO compared with renal normoxia. This process contributes to the increase in EPO production that is observed in response to anemia. In normal individuals with intact IRP1 function, iron deficiency reduces the amount of HIF2α formed and, therefore, restricts the amount of EPO produced, even under hypoxic conditions (middle panel). Therefore, renal HIF2α and EPO production are decreased in iron deficiency as compared with iron-replete conditions. In the IRP1 knockout condition (right panel), basal HIF2α and EPO production are increased under normal conditions, and iron deficiency exacerbates these already elevated levels, presumably by decreasing the activity of iron-containing prolyl-hydroxyase (smaller blue oval), even when the kidney is normoxic.

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