Ablation of intestinal divalent metal‐ion transporter‐1 produces iron‐deficiency anemia

Abstract

Divalent metal‐ion transporter‐1 (DMT1)—the product of the SLC11A2 gene—is a widely expressed iron transporter serving intestinal iron absorption and erythroid iron utilization. We tested the hypothesis that DMT1 is essential for intestinal absorption of iron by examining hematological variables, iron stores, and expression of iron‐related genes (by using real‐time qPCR) in a mouse model lacking intestinal DMT1 (i.e. DMT1int/int), males at age ≈ 120 days. Generation of the DMT1int/int model, by crossing floxed DMT1 and villin‐Cre transgenic lines, was described previously [Gunshin et al (2005) J. Clin. Investig.115, 1258–1266]. The DMT1int/int mouse exhibited a severe microcytic– hypochromic anemia—characterized by profound decreases in hematocrit, hemoglobin concentration (DMT1int/int, 2.3 ± SD 1.5 g/dL cf. wildtype, 14.6 ± 0.7 g/dL; n = 7–9), mean corpuscular volume, and serum iron—accompanied by cardiac hypertrophy, splenomegaly, and severely depleted nonheme iron stores (liver, spleen). mRNA expression of the brush‐border ferrireductase Cybrd1 was increased (30 ± 3)‐fold in enterocytes of DMT1int/int mice cf. wildtype mice (mean ± propagated SE, n = 3) and mRNA expression of the basolateral iron‐exporter ferroportin was increased (2.7 ± 1.0)‐fold. Liver Hamp1 (hepcidin) mRNA expression was depressed by 98% ± 42% in the DMT1int/int mouse cf. wildtype. Intraperitoneal iron injection corrected the hematological variables, iron stores, and mRNA expression levels in the DMT1int/int mouse. Our data reveal that tissue‐specific ablation of intestinal DMT1 produces an iron‐deficiency anemia, and confirm that DMT1 is critical for iron homeostasis in the mouse. PHS Grant DK080047