Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice.

Jana Frýdlová,Jan Krijt,Martin Vokurka,Jaroslav Truksa,Zuzana Rychtarčíková,Iuliia Gurieva

doi:10.1371/journal.pone.0186844

Abstract

Tmprss6-mutated mask mice display iron deficiency anemia and high expression of hepcidin. The aim of the study was to determine the effect of erythropoietin administration on proteins participating in the control of iron homeostasis in the liver and spleen in C57BL/6 and mask mice. Administration of erythropoietin for four days at 50 IU/mouse/day increased hemoglobin and hematocrit in C57BL/6 mice, no such increase was seen in mask mice. Erythropoietin administration decreased hepcidin expression in C57BL/6 mice, but not in mask mice. Erythropoietin treatment significantly increased the spleen size in both C57BL/6 and mask mice. Furthermore, erythropoietin administration increased splenic Fam132b, Fam132a and Tfr2 mRNA content. At the protein level, erythropoietin increased the amount of splenic erythroferrone and transferrin receptor 2 both in C57BL/6 and mask mice. Splenic ferroportin content was decreased in erythropoietin-treated mask mice in comparison with erythropoietin-treated C57BL/6 mice. In mask mice, the amount of liver hemojuvelin was decreased in comparison with C57BL/6 mice. The pattern of hemojuvelin cleavage was different between C57BL/6 and mask mice: In both groups, a main hemojuvelin band was detected at approximately 52 kDa; in C57BL/6 mice, a minor cleaved band was seen at 47 kDa. In mask mice, the 47 kDa band was absent, but additional minor bands were detected at approximately 45 kDa and 48 kDa. The results provide support for the interaction between TMPRSS6 and hemojuvelin in vivo; they also suggest that hemojuvelin could be cleaved by another as yet unknown protease in the absence of functional TMPRSS6. The lack of effect of erythropoietin on hepcidin expression in mask mice can not be explained by changes in erythroferrone synthesis, as splenic erythroferrone content increased after erythropoietin administration in both C57BL/6 and mask mice.

Highlights

Iron is present in many proteins and is indispensable for life
A minor fraction of patients with iron-deficiency anemia do not respond to oral iron administration, and this iron-refractory iron deficiency anemia can be caused by mutations in the TMPRSS6 gene [2]
We were interested in the effect of EPO on the synthesis of ERFE in the spleen, since spleen is the main site of mouse stress erythropoiesis [37,38], and in the effect of Tmprss6 mutation on HJV, since HJV is the proposed target of Tmprss6-related proteolytic activity [21]

Summary

Introduction

Iron is present in many proteins and is indispensable for life. About 75% of iron present in the human body is contained in hemoglobin, and lack of iron predictably leads to anemia. Iron-deficiency anemia is the most common form of anemia worldwide [1], and in the vast majority of cases it can be treated by iron supplementation. A minor fraction of patients with iron-deficiency anemia do not respond to oral iron administration, and this iron-refractory iron deficiency anemia can be caused by mutations in the TMPRSS6 gene [2]. Available clinical and experimental data demonstrate that functional TMPRSS6 is necessary for the appropriate regulation of hepcidin expression [2,3,4,5,6]

Objectives

Methods

Results

Conclusion