Patients with mutations in
divalent metal transporter-1 (DMT1), an intestinal nonheme
iron transporter, suffer from microcytic
anemia and hepatic
iron loading. DMT1 is also mutated in Belgrade rats, an animal model with a thalassemic-like disorder of microcytic
anemia with hyperferrinemia. However, aspects of hepatic
iron loading in this genetic model are not well characterized. To more fully define the Belgrade rat's
iron status, we compared the characteristics of homozygous (b/b) and heterozygous (b/+) rats fed an
iron-supplemented diet for 3 wk postweaning. Dietary supplementation with ferrous
iron improved the
anemia of b/b rats insofar as hematocrits increased from 0.13 (21-d-old) to 0.31 (42-d-old). However, hematocrits remained significantly lower than those of age-matched b/+ rats (0.36 and 0.41 in 21- and 42-d-old heterozygotes, respectively, P < 0.05). Wright's staining of b/b red cells confirmed the hypochromic microcytic nature of Belgrade rats'
anemia. The liver
iron concentration of 42-d-old b/b rats was greater than in age-matched b/+ rats (5.97 vs. 2.24 mumol/g, P < 0.05). Whereas Perls'
Prussian blue iron staining was evident in both periportal and centrilobular regions in 42-d-old b/b liver sections, no staining was observed in age-matched b/+ tissue sections. Quantitative real-time PCR analysis showed that expression of liver
hepcidin mRNA in 42-d-old b/b rats was 3-fold greater than age-matched b/+ rats. These results indicate that, similar to human patients with DMT1 mutations, Belgrade rats also display hepatic
iron loading. Our data suggest this condition arises from ineffective erythropoiesis.