A protective role of heme-regulated eIF2α kinase in cadmium-induced toxicity in erythroid cells

Abstract

Although a number of studies have demonstrated that cadmium (Cd) can incur damage to mature red cells, the potential injuries of Cd to erythroid progenitor cells have not been investigated thus far. Heme-regulated eIF2α kinase (Hri) is essential for translational regulation and survival of erythroid precursors in the setting of iron deficiency. Hri has been demonstrated to activate Atf4 signaling in reducing oxidative stress and in promoting erythroid differentiation during stress erythropoiesis. Here, we demonstrated that Cd significantly provoked cell death and suppressed erythroid differentiation of erythroid progenitor cells. Importantly, our results established a crucial role of Hri in ameliorating Cd-induced impairment to erythropoiesis. Upon Cd treatment, Hri-eIF2αP-Atf4 signaling was activated to protect cells from cell death and differentiation attenuation in Wt fetal liver erythroblasts; in contrast, Hri(-/-) erythroblasts suffered from enhanced oxidative stress, as evidenced by increased levels of reactive oxygen species (ROS) and consequentially elevated apoptosis. As for Cd administration in vivo, impaired erythropoiesis in bone marrow and dramatic extramedullary erythropoiesis in spleen were observed in Hri(-/-) mice. Taken together, our combined data highlighted a crucial role of Hri in protecting survival and differentiation of erythroid progenitor cells upon Cd treatment.

Keywords: As; Atf4; BM; CBC; Cadmium; Cd; Cell death; EPO; ER; Erythropoiesis; FBS; FITC; FL; H&E; HCT; HGB; HO-1; Heme-regulated eIF2α kinase; Hri; ICP-MS; KI; Ko; MCV; Oxidative stress; PE; RBC; ROS; UTR; bone marrow; cadmium; complete blood count; eIF2αP; endoplasmic reticulum; erythropoietin; fetal bovine serum; fetal liver; fluorescein isothiocyanate; hematocrit; hematoxylin and eosin; heme oxygenase-1; hemoglobin; inductively coupled plasma mass spectrometry; kinase insertion; knockout; mean corpuscular volume; phosphorylation of the α-subunit of eIF2; phycoerythrin; reactive oxygen species; red blood cells; sodium arsenite; transcriptional factor 4; untranslated region.