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 expressed in mucous, zymogenic, and parietal cells, we prepared mice with a null 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 reduced markedly in number. Net acid secretion in null mutants is reduced slightly relative to wild-type levels just before weaning and is abolished in adult animals. Although mature parietal cells are observed, and appear morphologically to be engaged in active acid secretion, many of the parietal cells are in various stages of degeneration. These results indicate that NHE2 is not required for acid secretion by the parietal cell, but is essential for its long-term viability. This suggests that the unique sensitivity of NHE2 to inhibition by extracellular H+, which would allow upregulation of its activity by the increased interstitial alkalinity that accompanies acid secretion, might enable this isoform to play a specialized role in maintaining the long-term viability of the parietal cell.
Schultheis
P J
PJ
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
Clarke
L L
LL
Meneton
P
P
Harline
M
M
Boivin
G P
GP
Stemmermann
G
G
Duffy
J J
JJ
Doetschman
T
T
Miller
M L
ML
Shull
G E
GE
D000143:Acids / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004247:DNA / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism; D005755:Gastrins / Q000032:analysis / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007536:Isomerism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010295:Parietal Cells, Gastric / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D010435:Pepsinogens / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000378:metabolism; D011247:Pregnancy; D011522:Protons; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism
D000143:Acids; D005755:Gastrins; D010435:Pepsinogens; D011522:Protons; D012333:RNA, Messenger; C513111:Slc9a2 protein, mouse; D017923:Sodium-Hydrogen Exchangers; D004247:DNA; D000251:Adenosine Triphosphatases; D011188:Potassium