title: Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model.
abstract: Hemolysis occurring in hematologic diseases is often associated with an iron loading anemia. This iron overload is the result of a massive outflow of hemoglobin into the bloodstream, but the mechanism of hemoglobin handling has not been fully elucidated. Here, in a congenital erythropoietic porphyria mouse model, we evaluate the impact of hemolysis and regenerative anemia on hepcidin synthesis and iron metabolism. Hemolysis was confirmed by a complete drop in haptoglobin, hemopexin and increased plasma lactate dehydrogenase, an increased red blood cell distribution width and osmotic fragility, a reduced half-life of red blood cells, and increased expression of heme oxygenase 1. The erythropoiesis-induced Fam132b was increased, hepcidin mRNA repressed, and transepithelial iron transport in isolated duodenal loops increased. Iron was mostly accumulated in liver and spleen macrophages but transferrin saturation remained within the normal range. The expression levels of hemoglobin-haptoglobin receptor CD163 and hemopexin receptor CD91 were drastically reduced in both liver and spleen, resulting in heme- and hemoglobin-derived iron elimination in urine. In the kidney, the megalin/cubilin endocytic complex, heme oxygenase 1 and the iron exporter ferroportin were induced, which is reminiscent of significant renal handling of hemoglobin-derived iron. Our results highlight ironbound hemoglobin urinary clearance mechanism and strongly suggest that, in addition to the sequestration of iron in macrophages, kidney may play a major role in protecting hepatocytes from iron overload in chronic hemolysis.
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Service Odontologie, Hôpital Universitaire, Université de Montpellier, France.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Millot
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.|Institut de Médecine Régénératrice et de Biothérapie-Hôpital Saint Eloi CHU Montpellier, Université de Montpellier, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Delaby
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Boualem
authors.initials: B
authors.lastname: Moulouel
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Lefebvre
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pilard
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ducrot
authors.affiliation: INSERM, Biothérapies des Maladies Génétiques et Cancers, U1035, F-33000 Bordeaux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Ged
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lettéron
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: de Franceschi
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.|Institut de Médecine Régénératrice et de Biothérapie-Hôpital Saint Eloi CHU Montpellier, Université de Montpellier, France.
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Deybach
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: De Verneuil
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.|Université Versailles Saint Quentin en Yvelines, France.
authors.forename: Saïd
authors.initials: S
authors.lastname: Lyoumi
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France herve.puy@aphp.fr zoubida.karim@inserm.fr.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
authors.affiliation: INSERM U1149/ERL CNRS 8252, Centre de Recherche sur l'Inflammation Paris Montmartre, 75018 Paris, France herve.puy@aphp.fr zoubida.karim@inserm.fr.|Université Paris Diderot, Bichat site, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Zoubida
authors.initials: Z
authors.lastname: Karim
mesh_terms: D000743:Anemia, Hemolytic / Q000097:blood / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D015415:Biomarkers; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism; D004920:Erythropoiesis; D015870:Gene Expression; D006418:Heme / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D064451:Hepcidins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000652:urine; D019190:Iron Overload / Q000209:etiology / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013154:Spleen / Q000502:physiology; D013312:Stress, Physiological
chemical_list: D015415:Biomarkers; D064451:Hepcidins; D006418:Heme; D007501:Iron