Ablation of intestinal brush‐border Na + /H + exchanger NHE3 impairs iron absorption in the mouse (900.1)

Divalent metal‐ion transporter‐1 (DMT1) is critical for intestinal iron absorption. DMT1 is energized by the H + electrochemical potential gradient but the provenance of the H + required to drive apical iron uptake is not known. To assess the role of the brush‐border acidic microclimate in aiding intestinal iron transport, we have examined iron homeostasis and intestinal iron handling in mouse models lacking the brush‐border Na + /H + exchangers NHE2 and NHE3. We found that liver nonheme iron stores (a preferred indicator of chronic iron status) were modestly depleted in NHE2‐null mice compared with wildtype mice. In animals stressed on a low‐iron diet, hematological and blood‐iron variables were no different between NHE2‐null and wildtype mice and we observed no difference in the expression of genes associated with iron metabolism. Liver nonheme iron stores were severely depleted (by 70–90%) in NHE3‐null mice compared with wildtype mice. We observed substantial decreases in serum iron and transferrin saturation in NHE3‐null mice but no overt anemia. mRNA expression of DMT1, the brush‐border ferrireductase Cybrd1, and the basolateral iron‐exporter ferroportin were each increased >10‐fold in NHE3‐null mice, and expression of liver Hamp1 (hepcidin) suppressed by over 99%, compared with wildtype. Absorption of 59 Fe (administered by intragastric gavage) was profoundly impaired in NHE3‐null mice but not NHE2‐null mice compared with wildtype. The low 59 Fe content of enterocytes in the NHE3‐null revealed a deficit in brush‐border iron uptake. Our data indicate that ablation of NHE3 severely impairs iron absorption and homeostasis in the mouse and suggest that the acidic microclimate drives DMT1‐mediated iron uptake at the intestinal brush border. Grant Funding Source : Supported by PHS Grant DK080047