Localization of Na+-HCO-3 cotransporter (NBC-1) variants in rat and human pancreas.
Mutations in Na(+)-HCO(3)(-) cotransporter (NBC-1) cause proximal renal tubular acidosis (pRTA) associated with ocular abnormalities. One pRTA patient had increased serum amylase, suggesting possible evidence of pancreatitis. To further delineate a link between NBC-1 inactivation and pancreatic dysfunction, immunohistochemical analysis was performed on rat and human pancreas using antibodies against kidney-type (kNBC-1) and pancreatic-type (pNBC-1) transporters. In rat pancreas, the anti-pNBC-1 antibody labeled acinar cells and both apical and basolateral membranes of medium and large duct cells. In human pancreas, on the other hand, the anti-pNBC-1 antibody did not label acinar cells, although it did label the basolateral membranes of the entire duct system. The labeling by anti-kNBC-1 antibody was detected in only a limited number of rat pancreatic duct cells. To examine the effects of pRTA-related mutations, R342S and R554H, on pNBC-1 function, we performed functional analysis and found that both mutants had reduced transport activities compared with the wild-type pNBC-1. These results indicate that pNBC-1 is the predominant variant that mediates basolateral HCO(3)(-) uptake into duct cells in both rat and human pancreas. The loss of pNBC-1 function is predicted to have significant impact on overall ductal HCO(3)(-) secretion, which could potentially lead to pancreatic dysfunction.
Satoh
Hiroaki
H
Department of Internal Medicine, Faculty of Medicine, Tokyo University, Japan.
Moriyama
Nobuo
N
Hara
Chiaki
C
Yamada
Hideomi
H
Horita
Shoko
S
Kunimi
Motoei
M
Tsukamoto
Kazuhisa
K
Iso-O
Naoyuki
N
Inatomi
Jun
J
Kawakami
Hayato
H
Kudo
Akihiko
A
Endou
Hitoshi
H
Igarashi
Takashi
T
Goto
Atsuo
A
Fujita
Toshiro
T
Seki
George
G
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D010182:Pancreatic Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000172:deficiency* / Q000235:genetics
D001639:Bicarbonates; D020033:Protein Isoforms; D012333:RNA, Messenger; C498898:SLC4A4 protein, human; C422004:Slc4a4 protein, rat; D027982:Sodium-Bicarbonate Symporters; D012964:Sodium