Intestinal brush-border Na+/H+ exchanger-3 drives H+-coupled iron absorption in the mouse

Area of Science:

• Physiology
• Molecular Biology
• Gastroenterology

Background:

• Divalent metal-ion transporter-1 (DMT1) mediates nonheme iron uptake in the intestine, driven by the proton (H+) electrochemical gradient.
• The origin of the H+ gradient powering DMT1 in vivo remains unclear.
• Brush-border Na+/H+ exchangers (NHE) are potential regulators of this gradient.

Purpose of the Study:

• To investigate the role of NHE isoforms, specifically NHE2 and NHE3, in maintaining iron homeostasis and intestinal iron handling.
• To determine if NHE isoforms contribute to the H+ gradient driving DMT1-mediated iron uptake.

Main Methods:

• Analysis of iron homeostasis and intestinal iron handling in mice genetically deficient in NHE2 (NHE2(-/-)) or NHE3 (NHE3(-/-)).
• Assessment of hematological parameters, liver iron stores, and gene expression related to iron metabolism.
• Measurement of (59)Fe absorption following oral administration.

Main Results:

• NHE2(-/-) mice showed minor liver iron depletion under stress but no significant changes in blood iron or related gene expression.
• NHE3(-/-) mice exhibited significantly depleted liver iron stores and decreased blood iron variables, without overt anemia.
• Intestinal DMT1, cytochrome b reductase-1, and ferroportin expression were upregulated, while liver hepcidin (Hamp1) was suppressed in NHE3(-/-) mice.
• Oral (59)Fe absorption was substantially impaired in NHE3(-/-) mice compared to wild-type controls.

Conclusions:

• NHE3 plays a significant role in generating the H+ electrochemical gradient necessary for DMT1-mediated intestinal iron uptake.
• Ablation of NHE3 severely impacts iron absorption and homeostasis, highlighting its critical function in the intestinal brush border.