Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model

Millot, Sarah; Delaby, Constance; Moulouel, Boualem; Lefèbvre, Thibaud; Pilard, Nathalie; Ducrot, Nicolas; Ged, Cécile; Lettéron, Philippe; Franceschi, Lucia De; Deybach, Jean Charles; Beaumont, Carole; Gouya, Laurent; Verneuil, Hubert de; Lyoumi, Saı̈d; Puy, Hervé; Karim, Zoubida

doi:10.3324/haematol.2016.151621

Cited by 15 publications

(16 citation statements)

References 40 publications

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“…Iron-regulated induction of ferritin expression in hemolytic disorders is usually associated with an increased amount of iron stored in a non-toxic form within ferritin molecules. However, in contrast to a congenital erythropoietic porphyria, a chronic mouse model of hemolytic disorder 43 , we failed to detect any rise in iron content in the kidneys of mouse neonates by staining renal sections with Prussian blue, even during the period of highest hemolysis (days 3–7 after birth). Although this lack of staining does not exclude limited iron accumulation in ferritin (which is below the detection limit of the method), it certainly excludes the occurrence of heavy iron deposits observed in the kidneys during pathological hemolytic conditions 9–11,50 .…”

Section: Discussioncontrasting

confidence: 89%

“…It is noteworthy that the neonatal pattern of Fpn expression in the renal proximal tubule epithelium matches the expression pattern of other iron- and heme-related proteins analyzed in this study. Increase in protein abundance of Fpn, HO1 and ferritin in the cortical part of the kidney was reported in adult mice with severe hemolytic disorder such as congenital erythropoietic porphyria 43 . Interestingly, it appears that renal Fpn expression in mouse neonates is not systematically regulated by hepcidin, similarly to previous reports 52,53 , as hepatic expression of the Hamp gene was induced only on day 3 postpartum and during consecutive days of neonatal period was barely detectable.…”

Section: Discussionmentioning

confidence: 94%

“…Hb, if not bound by Hp, readily passes through the glomerular filter to enter the primary urine, from where it is rapidly cleared by the renal proximal epithelium 5,41 via the multi-ligand hetero-dimeric receptor-complex megalin/cubilin 42 . Renal uptake of hemoglobin by megalin/cubilin complex has been reported in hemolytic conditions 43 . Herein, we demonstrate for the first time that the expression of these two receptors in renal proximal tubules gradually decreases with age in mouse neonates, suggesting their involvement in cellular reabsorption of hemoglobin during neonatal hemolysis.…”

Section: Discussionmentioning

confidence: 99%

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Role of the kidneys in the redistribution of heme-derived iron during neonatal hemolysis in mice

Bednarz

Lipiński

Starzyński

et al. 2019

Sci Rep

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Moderate intravascular hemolysis is a common condition in newborns. It is followed by the accumulation of bilirubin, which is a secondary product of the activity of heme oxygenase-1, an enzyme that catalyzes the breakdown of heme released from disrupted erythrocytes and taken up by hepatic macrophages. Although these cells are a major site of enzymatic heme breakdown in adults, we show here that epithelial cells of proximal tubules in the kidneys perform the functions of both heme uptake and catabolism in mouse neonates. A time-course study examining mouse pups during the neonatal period showed a gradual recovery from hemolysis, and concomitant decreases in the expression of heme-related genes and non-heme iron transporters in the proximal tubules. By adjusting the expression of iron-handling proteins in response to the disappearance of hemolysis in mouse neonates, the kidneys may play a role in the detoxification of iron and contribute to its recirculation from the primary urine to the blood.

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Section: Discussioncontrasting

confidence: 89%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Role of the kidneys in the redistribution of heme-derived iron during neonatal hemolysis in mice

Bednarz

Lipiński

Starzyński

et al. 2019

Sci Rep

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“…In a rat kidney cell model, megalin regulation by iron and the functional competition between TfR1 and megalin was suggested [ 46 ]. Recently also cubilin upregulation was observed in a mouse-model for hemolytic anemia and this was accompanied by increased function of the megalin/cubilin complex [ 47 ]. A patient with two mutations in the megalin gene, which led to a mostly intracellular location of megalin and absence of membrane megalin, had elevated urinary levels of cubilin and type 3 carbonic anhydrase due to shedding of these proteins [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Orchestrated regulation of iron trafficking proteins in the kidney during iron overload facilitates systemic iron retention

et al. 2018

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The exact route of iron through the kidney and its regulation during iron overload are not completely elucidated. Under physiologic conditions, non-transferrin and transferrin bound iron passes the glomerular filter and is reabsorbed through kidney epithelial cells, so that hardly any iron is found in the urine. To study the route of iron reabsorption through the kidney, we analyzed the location and regulation of iron metabolism related proteins in kidneys of mice with iron overload, elicited by iron dextran injections. Transferrin Receptor 1 was decreased as expected, following iron overload. In contrast, the multi-ligand hetero-dimeric receptor-complex megalin/cubilin, which also mediates the internalization of transferrin, was highly up-regulated. Moreover, with increasing iron, intracellular ferritin distribution shifted in renal epithelium from an apical location to a punctate distribution throughout the epithelial cells. In addition, in contrast to many other tissues, the iron exporter ferroportin was not reduced by iron overload in the kidney. Iron accumulated mainly in interstitial macrophages, and more prominently in the medulla than in the cortex. This suggests that despite the reduction of Transferrin Receptor 1, alternative pathways may effectively mediate re-absorption of iron that cycles through the kidney during parenterally induced iron-overload. The most iron consuming process of the body, erythropoiesis, is regulated by the renal erythropoietin producing cells in kidney interstitium. We propose, that the efficient re-absorption of iron by the kidney, also during iron overload enables these cells to sense systemic iron and regulate its usage based on the systemic iron state.

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“…However, IFNα has been shown to induce hepcidin expression in a human hepatoma cell line (10) as well as in mice (11). In addition, RBV administration often induces hemolytic anemia (12) and affects iron metabolism because of reactive erythropoiesis (13,14).…”

Section: Introductionmentioning

confidence: 99%

Changes in the Serum Hepcidin-to-ferritin Ratio with Erythroferrone after Hepatitis C Virus Eradication Using Direct-acting Antiviral Agents

et al. 2019

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Objective Hepcidin is a master iron regulator hormone produced by the liver, but precise mechanism underlying its involvement in iron overload in hepatitis C virus (HCV) infection remains unclear. We investigated the serum hepcidin levels against iron overload before and after HCV eradication. Methods We prospectively investigated the iron metabolism characteristics in 24 patients with HCV genotype 1b infection before and after treatment. We also assessed the serum erythroferrone (ERFE) levels to investigate its association with iron metabolism changes. Patients were treated with Ledipasvir 90 mg and Sofosbuvir 400 mg once daily for 12 weeks and observed for 12 more weeks in order to evaluate their sustained virological response. Results Serum hepcidin levels at baseline were in the normal range, although serum ferritin levels were increased. After HCV eradication, both serum ferritin and hepcidin levels were significantly decreased at 24 weeks from baseline (p<0.001, p=0.006, respectively). However, the serum hepcidin-to-ferritin ratios were significantly increased (p<0.001). In addition, the serum ERFE levels were significantly decreased (p<0.001). Increases in the serum hepcidin-to-ferritin ratios were correlated with decreases in the serum ERFE levels (ρ=−0.422, p=0.039). Conclusion Serum hepcidin levels were relatively low against ferritin levels in HCV infection. However, after HCV eradication, the serum hepcidin-to-ferritin ratios were increased. These results indicate the improvement of inadequate hepcidin secretion against iron overload after HCV eradication. Downregulation of ERFE may have affected the improvement of iron metabolism.

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Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model

Cited by 15 publications

References 40 publications

Role of the kidneys in the redistribution of heme-derived iron during neonatal hemolysis in mice

Role of the kidneys in the redistribution of heme-derived iron during neonatal hemolysis in mice

Orchestrated regulation of iron trafficking proteins in the kidney during iron overload facilitates systemic iron retention

Changes in the Serum Hepcidin-to-ferritin Ratio with Erythroferrone after Hepatitis C Virus Eradication Using Direct-acting Antiviral Agents

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