TARGETED DISRUPTION OF THE MURINE NA+ H+ EXCHANGER ISOFORM-2 GENE CAUSES REDUCED VIABILITY OF GASTRIC PARIETAL-CELLS AND LOSS OF NET ACID-SECRETION/

Multiple isoforms of the Na+/H+ exchanger (NHE) are expressed at high levels in gastric epithelium, but the physiological role of individual isoforms is unclear, To study the function of NHE2, which is expresse d in mucous, zymogenic, and parietal cells, we prepared mice with a nu ll mutation in the NHE2 gene, Homozygous null mutants exhibit no overt disease phenotype, but the cellular composition of the oxyntic mucosa of the gastric corpus is altered, with parietal and zymogenic cells r educed markedly in number, Net acid secretion in null mutants is reduc ed slightly relative to wild-type levels just before weaning and is ab olished in adult animals. Although mature parietal cells are observed, and appear morphologically to be engaged in active acid secretion, ma ny of the parietal cells are in various stages of degeneration. These results indicate that NHE2 is not required for acid secretion by the p arietal cell, but is essential for its long-term viability. This sugge sts that the unique sensitivity of NHE2 to inhibition by extracellular H+, which would allow upregulation of its activity by the increased i nterstitial alkalinity that accompanies acid secretion, might enable t his isoform to play a specialized role in maintaining the long-term vi ability of the parietal cell.