Inefficient chronic activation of parietal cells in Ae2a,b(-/-) mice.
In parietal cells, basolateral Ae2 Cl(-)/HCO(3)(-) exchanger (Slc4a2) appears to compensate for luminal H(+) pumping while providing Cl(-) for apical secretion. In mouse and rat, mRNA variants Ae2a, Ae2b1, Ae2b2, and Ae2c2 are all found in most tissues (although the latter at very low levels), whereas Ae2c1 is restricted to the stomach. We studied the acid secretory function of gastric mucosa in mice with targeted disruption of Ae2a, Ae2b1, and Ae2b2 (but not Ae2c) isoforms. In the oxyntic mucosa of Ae2(a,b)(-/-) mice, total Ae2 protein was nearly undetectable, indicating low gastric expression of the Ae2c isoforms. In Ae2(a,b)(-/-) mice basal acid secretion was normal, whereas carbachol/histamine-stimulated acid secretion was impaired by 70%. These animals showed increased serum gastrin levels and hyperplasia of G cells. Immunohistochemistry and electron microscopy revealed baseline activation of parietal cells with fusion of intracellular H(+)/K(+)-ATPase-containing vesicles with the apical membrane and degenerative changes (but not substantial apoptosis) in a subpopulation of these cells. Increased expression of proliferating cell nuclear antigen in the oxyntic glands suggested enhanced Ae2(a,b)(-/-) parietal cell turnover. These data reveal a critical role of Ae2a-Ae2b1-Ae2b2 isoforms in stimulated gastric acid secretion whereas residual Ae2c isoforms could account to a limited extent for basal acid secretion.
Recalde
Sergio
S
Laboratory of Experimental Hepatology, Academic Medical Center Liver Center, Amsterdam, The Netherlands.
Muruzábal
Francisco
F
Looije
Norbert
N
Kunne
Cindy
C
Burrell
María A
MA
Sáez
Elena
E
Martínez-Ansó
Eduardo
E
Salas
January T
JT
Mardones
Pablo
P
Prieto
Jesús
J
Medina
Juan F
JF
Elferink
Ronald P J Oude
RP
D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D027963:Chloride-Bicarbonate Antiporters; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism; D005755:Gastrins / Q000097:blood; D015870:Gene Expression; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D046529:Microscopy, Electron, Transmission; D010295:Parietal Cells, Gastric / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064606:SLC4A Proteins; D014158:Transcription, Genetic
D027321:Anion Transport Proteins; D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D005755:Gastrins; D020033:Protein Isoforms; D012333:RNA, Messenger; D064606:SLC4A Proteins; C579495:Slc4a2 protein, mouse; C579494:Slc4a2 protein, rat