Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 Na+/H+ exchanger.
The NHE4 Na+/H+ exchanger is abundantly expressed on the basolateral membrane of gastric parietal cells. To test the hypothesis that it is required for normal acid secretion, NHE4-null mutant (NHE4-/-) mice were prepared by targeted disruption of the NHE4 (Slc9a4) gene. NHE4-/- mice survived and appeared outwardly normal. Analysis of stomach contents revealed that NHE4-/- mice were hypochlorhydric. The reduction in acid secretion was similar in 18-day-old, 9-week-old, and 6-month-old mice, indicating that the hypochlorhydria phenotype did not progress over time, as was observed in mice lacking the NHE2 Na+/H+ exchanger. Histological abnormalities were observed in the gastric mucosa of 9-week-old NHE4-/- mice, including sharply reduced numbers of parietal cells, a loss of mature chief cells, increased numbers of mucous and undifferentiated cells, and an increase in the number of necrotic and apoptotic cells. NHE4-/- parietal cells exhibited limited development of canalicular membranes and a virtual absence of tubulovesicles, and some of the microvilli had centrally bundled actin. We conclude that NHE4, which may normally be coupled with the AE2 Cl-/HCO3- exchanger, is important for normal levels of gastric acid secretion, gastric epithelial cell differentiation, and development of secretory canalicular and tubulovesicular membranes.
Gawenis
Lara R
LR
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Greeb
Jeannette M
JM
Prasad
Vikram
V
Grisham
Christina
C
Sanford
L Philip
LP
Doetschman
Thomas
T
Andringa
Anastasia
A
Miller
Marian L
ML
Shull
Gary E
GE
D000126:Achlorhydria / Q000473:pathology; D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005091:Exons; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009336:Necrosis; D010295:Parietal Cells, Gastric / Q000166:cytology / Q000648:ultrastructure; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
D018076:DNA, Complementary; D005755:Gastrins; D012333:RNA, Messenger; C489906:Slc9a4 protein, mouse; D017923:Sodium-Hydrogen Exchangers; D012313:RNA