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    • regadenoson Hepcidin expression was not affected

    2022-05-16

    Hepcidin expression was not affected under GlyT1 inhibition. Hepcidin downregulation is well documented in conditions of ineffective erythropoiesis and dyserythropoietic anemias, including sideroblastic anemia 33, 34. Systemic iron acquisition under these types of anemia is obviously independent from the status of the existing iron stores (iron overload anemia). The mechanisms by which erythropoietic activity modulates the iron supply remain, however, incompletely understood. A number of mediators released by erythroblasts have been identified as strong co-regulators of hepcidin expression, with significant differences in expression activity between regenerative and ineffective erythropoiesis 33, 35. Hemolytic anemias, even with massive peripheral destruction of erythrocytes such as sickle cell anemia, do not stimulate intestinal iron regadenoson 36, 37, 38 and do not significantly depress hepcidin synthesis, although the regenerative erythropoietic activity is high. However, these conditions are characterized by the absence of ineffective erythropoiesis and thus a significantly lower iron turnover within the erythron. This contrasts to the condition of ineffective erythropoiesis, in which an abnormal rate of apoptosis within maturing erythroblasts causes an overproportionally high intra-marrow iron release and turnover. The regulatory pathways of anemia with systemic iron acquisition are therefore distinct from the conditions seen under the inhibition of GlyT1. The data also provide experimental evidence about the central regulatory role of hepcidin for iron tissue distribution 39, 40. When hepcidin is high, ferroportin is degraded, iron export from macrophages is blocked, and iron is thus preferentially retained and stored in spleen macrophages [41]. At low hepcidin concentrations, ferroportin transporters are active, iron is exported from macrophages, and iron stores in hepatocytes are activated [42]. Although hepcidin activity was not altered directly by GlyT1 inhibition, hepcidin showed a significant regulatory role in tissue distribution of storage iron when heme biosynthesis and iron reutilization were reduced. Indeed, a preferential spleen but low liver iron deposition was noted in rats under GlyT1 inhibition at hepcidin expression levels at the higher range of normal. In contrast, rats with a comparable increased pool of storage iron but concurrent hepcidin expression rates at the lower range of normal showed elevated liver iron scores but low spleen iron deposition. High serum ferritin concentration correlated preferentially with liver iron deposition, but ferritin was relatively insensitive for spleen hemosiderosis. Because serum ferritin reflects the actual synthesis rate of tissue ferritin and thus steady-state storage iron bioavailability, it is well established that serum ferritin concentration does not accurately reflect total hemosiderin iron stores [43]. This clearly explains the striking discrepancy between the pronounced spleen hemosiderosis and the only modest and statistically insignificant elevation of serum ferritin in this study. The extent to which other confounding factors have interfered in this study with iron regulatory pathways remains unknown. The moderate increase in mean control group serum ferritin, based on abnormal high values in a few individual animals, might point to a recently identified mutation in TfR-2, which has been associated with the sporadically observed iron overload pathology of Wistar rats [44]. Even though the prevalence in the breeding line used here is unknown, such a genetic predisposition might have not only accounted for the observed changes in control animals, but may have also interfered with the GlyT1-induced iron retention, thereby contributing to the interindividual variability of serum ferritin, hepcidin expression, and spleen and liver iron load in treated animals. An imbalanced heme–globin interregulation leading to excess of either free heme or globin chains is the well-established pathogenesis of a broad spectrum of hematological diseases such as beta-thalassemia or erythropoietic porphyria. Delayed globin transcription with an associated excess of free heme has been identified recently in bone marrow culture systems from patients with Diamand-Blackfan anemia and del(5) myelodysplastic syndrome as the causal reason for the ineffective erythropoiesis [45]. Those studies also provided experimental evidence that inhibition of heme synthesis could improve erythroblast survival. The selective inhibition of heme biosynthesis with an undisturbed systemic iron homeostasis by targeting GlyT1 might provide a promising therapeutic concept for such disorders.