Exacerbation of Neonatal Hemolysis and Impaired Renal Iron Handling in Heme Oxygenase 1-Deficient Mice.

Aleksandra Bednarz,Kacper Kowalski,Sylwia Herman,Alicja Józkowicz,Małgorzata Lenartowicz,Rafał R Starzyński,Rafał Mazgaj,Aneta Jończy,Paweł Lipiński,Ewelina Gruca,Zbigniew Baster,Mateusz Szudzik,Izabela Kraszewska,Zenon Rajfur,Mateusz Tomczyk

doi:10.3390/ijms21207754

Aleksandra Bednarz, Kacper Kowalski + Show 13 more

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https://doi.org/10.3390/ijms21207754

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Abstract

In most mammals, neonatal intravascular hemolysis is a benign and moderate disorder that usually does not lead to anemia. During the neonatal period, kidneys play a key role in detoxification and recirculation of iron species released from red blood cells (RBC) and filtered out by glomeruli to the primary urine. Activity of heme oxygenase 1 (HO1), a heme-degrading enzyme localized in epithelial cells of proximal tubules, seems to be of critical importance for both processes. We show that, in HO1 knockout mouse newborns, hemolysis was prolonged despite a transient state and exacerbated, which led to temporal deterioration of RBC status. In neonates lacking HO1, functioning of renal molecular machinery responsible for iron reabsorption from the primary urine (megalin/cubilin complex) and its transfer to the blood (ferroportin) was either shifted in time or impaired, respectively. Those abnormalities resulted in iron loss from the body (excreted in urine) and in iron retention in the renal epithelium. We postulate that, as a consequence of these abnormalities, a tight systemic iron balance of HO1 knockout neonates may be temporarily affected.

Highlights

Heme oxygenase 1 (HO1, coded by the Hmox1 gene) is an inducible, stress-responsive, multifunctional enzyme playing an important role in inflammation and iron homeostasis
In 11 day old knockouts, weakening hemolysis was accompanied by the overall recovery from the decline in red blood cells (RBC) status, as RBC indices returned to normal values observed in age-matched WT mice
Under intravascular hemolysis conditions, such as chronic hereditary and acquired hemolytic anemias, kidneys participate in the management of iron released from disrupted erythrocytes to the blood plasma [27,28,29,30]

Summary

Introduction

Heme oxygenase 1 (HO1, coded by the Hmox gene) is an inducible, stress-responsive, multifunctional enzyme playing an important role in inflammation and iron homeostasis. It catabolizes free heme, an iron protoporphyrin (IX), into equimolar amounts of ferrous iron (Fe2+), carbon monoxide (CO), and biliverdin [1]. HO1 by degrading heme contributes to heme homeostasis and to the protection against free heme-induced toxicity This latter function requires the co-expression of H-ferritin, which, by sequestering ferrous iron released from the protoporphyrin IX ring, neutralizes their pro-oxidant effects [4]. This pathway of heme iron recycling represents the main physiological route of iron egress in the body and, HO1 is a key enzyme in systemic iron turnover

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