Erythropoietin and iron—a conflicted alliance?
2018; Elsevier BV; Volume: 94; Issue: 5 Linguagem: Inglês
10.1016/j.kint.2018.07.027
ISSN1523-1755
Autores Tópico(s)Iron Metabolism and Disorders
ResumoSuzuki et al. analyzed a mouse model of erythropoietin-deficient anemia to show that during iron overload renal interstitial fibroblasts accumulate iron, and this impairs the hypoxia-driven transcription of the erythropoietin gene. The authors show that excess iron decreases levels of hypoxia-inducible transcription factor 2α (HIF2α), the main driver of erythropoietin production in hypoxia and anemia. The work advances our understanding of the effect of iron on hypoxia signaling, but its implications for anemia treatment are less clear. Suzuki et al. analyzed a mouse model of erythropoietin-deficient anemia to show that during iron overload renal interstitial fibroblasts accumulate iron, and this impairs the hypoxia-driven transcription of the erythropoietin gene. The authors show that excess iron decreases levels of hypoxia-inducible transcription factor 2α (HIF2α), the main driver of erythropoietin production in hypoxia and anemia. The work advances our understanding of the effect of iron on hypoxia signaling, but its implications for anemia treatment are less clear. Erythropoiesis absolutely requires 2 factors, iron and erythropoietin. Iron is the essential oxygen-binding moiety in hemoglobin, while erythropoietin is required for the survival and differentiation of erythroid precursors. Both of these factors are also regulators of erythropoiesis. When iron or erythropoietin is pathologically deficient, erythropoiesis decreases. Conversely, excess erythropoietin or iron act as stimuli for erythropoiesis. While the stimulatory effect of erythropoietin in nonanemic subjects is well known and dramatic, that of iron excess is more subtle, manifested as a slight but measurable increase in hemoglobin concentration in patients with iron overload from hereditary hemochromatosis1Beutler E. Felitti V. Gelbart T. Waalen J. Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry.Br J Haematol. 2003; 120: 887-893Crossref PubMed Scopus (61) Google Scholar and a more prominent increase in hemoglobin concentration in the various mouse models of this disorder. A different kind of interaction between iron and erythropoietin has emerged from clinical observations in patients with anemia associated with end-stage kidney disease. In response to evidence of harm associated with aggressive treatment of anemia with erythropoietin derivatives, and reacting to subsequent economic incentives to decrease the doses of these agents, nephrologists have empirically established that i.v. iron administration dose-dependently increases the erythropoiesis-stimulatory effect of erythropoietin.2Shirazian S. Grant C. Miller I. Fishbane S. How can erythropoeitin-stimulating agent use be reduced in chronic dialysis patients?.Semin Dial. 2013; 26: 534-536Crossref PubMed Scopus (4) Google Scholar The multiple potential reasons for the enhancement of the effectiveness of erythropoietin by iron include reversing systemic iron deficiency, providing extra iron to match the high transient demand for iron after each dose of erythropoietin (treating "functional" iron deficiency), and, by loading macrophages with iron, overpowering the blockade of macrophage iron export by hepcidin, whose concentrations are increased by inflammation and deficient renal excretion. Macrophages are the main site of iron accumulation in patients treated with i.v. iron, and they are remarkably resistant to its potentially injurious effects, perhaps explaining why there has not yet been a definitive signal of harm from even high-dose i.v. iron dosing. Nevertheless, the optimal dosing of iron to preserve its benefits and avoid any long-term harm has not been established.2Shirazian S. Grant C. Miller I. Fishbane S. How can erythropoeitin-stimulating agent use be reduced in chronic dialysis patients?.Semin Dial. 2013; 26: 534-536Crossref PubMed Scopus (4) Google Scholar Adding to a list of potential concerns, Suzuki et al. (2018)3Suzuki N. Matsuo-Tezuka Y. Sasaki Y. et al.Iron attenuates erythropoietin production by decreasing hypoxia-inducible transcription factor 2α concentrations in renal interstitial fibroblasts.Kidney Int. 2018; 94: 900-911Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar now report that iron overload may have an inhibitory effect on erythropoietin production in the kidneys. The studies have been performed in a mouse model of severe erythropoietin deficiency in which the native erythropoietin gene was replaced by a reporter gene that reflects its transcriptional regulation but does not generate functional erythropoietin. To rescue these mice from dying of anemia, the mice were engineered to also express a hypoactive erythropoietin gene construct in the liver. As expected, such mice were severely anemic (hemoglobin: ∼4 g/dl). The authors found that 10 mg of iron-dextran injected i.p. for 5 consecutive days induced erythropoiesis driven by the hypoactive hepatic erythropoietin gene by about 1 g/dl through an unknown mechanism, but the same dose of iron given for 2 days only slightly but not significantly increased hemoglobin. Remarkably, the renal interstitial fibroblasts, which normally would make most of the erythropoietin, accumulated iron, and the expression of the erythropoietin reporter in these cells was suppressed. A qualitatively similar but smaller suppressive effect of iron on the renal erythropoietin reporter was elicited by feeding these mice an iron overload diet. Conversely, dietary iron deficiency increased the expression of the erythropoietin reporter in the kidneys. The suppressive effect of parenteral iron on erythropoietin production was also seen in wild-type mice treated with the prolyl hydroxylase inhibitor compound GSK360A, indicating that it is not particular to the erythropoietin-deficient mouse model (Figure 1). What is the mechanism of renal erythropoietin suppression by iron accumulation in renal interstitial fibroblasts? The authors provide a partial answer, by documenting that iron administration decreased the levels of HIF, the hypoxia-inducible transcription factor that drives erythropoietin production. The cellular concentration of its subunit HIF2α is normally increased by hypoxia, predominantly because the lack of oxygen prevents HIF2α destruction triggered by oxygen-dependent hydroxylation of 2 of its prolines by HIF prolyl hydroxylases (PHDs). The severely anemic erythropoietin-deficient mice have hypoxic renal interstitium, with high levels of nuclear HIF2α at baseline. As documented by the authors, iron administration decreased HIF2α concentration, and iron deficiency enhanced it. An iron-dependent role for HIF2α has previously been observed in the context of iron absorption in the duodenum, where the increase in iron transporters during iron deficiency depended in part on HIF2α.4Shah Y.M. Matsubara T. Ito S. et al.Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency.Cell Metab. 2009; 9: 152-164Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 5Taylor M. Qu A. Anderson E.R. et al.Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice.Gastroenterology. 2011; 140: 2044-2055Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar In studies in human volunteers, i.v. iron administration acutely blunted hypoxic pulmonary vasoconstriction, and iron chelator deferoxamine enhanced it,6Smith T.G. Balanos G.M. Croft Q.P. et al.The increase in pulmonary arterial pressure caused by hypoxia depends on iron status.J Physiol. 2008; 586: 5999-6005Crossref PubMed Scopus (120) Google Scholar providing another example in which iron opposes the physiologic effects of hypoxia and iron deficiency enhances them. The mechanistic trail stops here, but I will speculate that the inhibitory effect of iron excess is mediated by its enhancement of PHD activity that marks HIF2α for destruction (Figure 1). Although PHDs are conventionally thought of as oxygen sensors, PHD activity depends not only on oxygen but also on 2 cofactors, iron and 2-oxoglutarate (also called α-ketoglutarate). It is therefore possible that cellular iron concentrations can regulate PHD activity either directly, if cellular iron is limiting for their catalytic activity, or indirectly by generating reactive oxygen species, or through the effect of iron on cellular energy metabolism and the generation of the PHD cofactor 2-oxoglutarate or PHD inhibitors succinate or fumarate.7Mole D.R. Iron homeostasis and its interaction with prolyl hydroxylases.Antiox Redox Signal. 2010; 12: 445-458Crossref PubMed Scopus (65) Google Scholar The implications of this well-performed study for the clinical nephrologist are less clear. Unlike in the mouse model of erythropoietin deficiency, the untreated anemia of chronic kidney diseases is seriously exacerbated by iron deficiency, inflammation, and the presence of uremic toxins.8Koury M.J. Haase V.H. Anaemia in kidney disease: harnessing hypoxia responses for therapy.Nat Rev Nephrol. 2015; 11: 394-410Crossref PubMed Scopus (183) Google Scholar In this context, iron therapy promotes iron delivery to erythrocyte precursors, explaining its well-established efficacy in anemia of end-stage chronic kidney diseases. Another reason for interpretive caution is that the pattern of specific iron deposition in renal interstitial fibroblasts has not been described in humans.9Van Raaij S. van Swelm R. Bouman K. et al.Tubular iron deposition and iron handling proteins in human healthy kidney and chronic kidney disease.Sci Rep. 2018; 8: 9353Crossref PubMed Scopus (50) Google Scholar Differences in the tissue patterns of iron loading between mice and humans are well-documented in genetic hemochromatosis: pancreatic islet cells load with iron in humans but not in mice. However, dietary iron loading in the mouse model of erythropoietin deficiency suppressed renal erythropoietin reporter even without detectable iron deposition in the interstitium, indicating that milder iron overload of the interstitial fibroblasts may be sufficient to impair erythropoietin production. Despite these caveats, clinicians would be well-advised to exercise therapeutic caution in early stages of chronic renal disease, in which excessive iron treatment could impair erythropoietin production. Clinical researchers should examine human renal biopsy and autopsy specimens for evidence of iron accumulation in the renal interstitium, using enhanced iron staining techniques, to establish whether interstitial iron accumulation also occurs in humans. Functional studies of the effect of i.v. iron administration on erythropoietin production in humans may also be feasible. If and when PHD inhibitors, currently in phase 2 and 3 clinical trials, enter clinical practice, the concern about the adverse effects of iron on erythropoietin production may wane, as less medicinal iron may be required to support the activity of these new drugs.8Koury M.J. Haase V.H. Anaemia in kidney disease: harnessing hypoxia responses for therapy.Nat Rev Nephrol. 2015; 11: 394-410Crossref PubMed Scopus (183) Google Scholar Relevant to the subject matter of this commentary, TG is a consultant to, and recipient of, research grants from Akebia and Keryx Pharma, and is a consultant to Vifor. Iron attenuates erythropoietin production by decreasing hypoxia-inducible transcription factor 2α concentrations in renal interstitial fibroblastsKidney InternationalVol. 94Issue 5PreviewIron is an essential mineral for oxygen delivery and for a variety of enzymatic activities, but excessive iron results in oxidative cytotoxicity. Because iron is primarily used in red blood cells, defective erythropoiesis caused by loss of the erythroid growth factor erythropoietin (Epo) elevates iron storage levels in serum and tissues. Here, we investigated the effects of iron in a mouse model of Epo-deficiency anemia, in which serum iron concentration was significantly elevated. We found that intraperitoneal injection of iron-dextran caused severe iron deposition in renal interstitial fibroblasts, the site of Epo production. Full-Text PDF Open Archive
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