Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis.
Proximal renal tubular acidosis associated with ocular abnormalities such as band keratopathy, glaucoma, and cataracts is caused by mutations in the Na(+)-HCO(3)(-) cotransporter (NBC-1). However, the mechanism by which NBC-1 inactivation leads to such ocular abnormalities remains to be elucidated. By immunological analysis of human and rat eyes, we demonstrate that both kidney type (kNBC-1) and pancreatic type (pNBC-1) transporters are present in the corneal endothelium, trabecular meshwork, ciliary epithelium, and lens epithelium. In the human lens epithelial (HLE) cells, RT-PCR detected mRNAs of both kNBC-1 and pNBC-1. Although a Na(+)-HCO(3)-cotransport activity has not been detected in mammalian lens epithelia, cell pH (pH(i)) measurements revealed the presence of Cl(-)-independent, electrogenic Na(+)-HCO(3)-cotransport activity in HLE cells. In addition, up to 80% of amiloride-insensitive pH(i) recovery from acid load in the presence of HCO(3)(-)/CO(2) was inhibited by adenovirus-mediated transfer of a specific hammerhead ribozyme against NBC-1, consistent with a major role of NBC-1 in overall HCO(3)-transport by the lens epithelium. These results indicate that the normal transport activity of NBC-1 is indispensable not only for the maintenance of corneal and lenticular transparency but also for the regulation of aqueous humor outflow.
Usui
T
T
Department of Ophthalmology, Faculty of Medicine, Tokyo University, Bunkyo-ku, Tokyo, Japan.
Hara
M
M
Satoh
H
H
Moriyama
N
N
Kagaya
H
H
Amano
S
S
Oshika
T
T
Ishii
Y
Y
Ibaraki
N
N
Hara
C
C
Kunimi
M
M
Noiri
E
E
Tsukamoto
K
K
Inatomi
J
J
Kawakami
H
H
Endou
H
H
Igarashi
T
T
Goto
A
A
Fujita
T
T
Araie
M
M
Seki
G
G
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000141:Acidosis, Renal Tubular / Q000150:complications* / Q000235:genetics; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002386:Cataract / Q000209:etiology* / Q000235:genetics; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D003315:Cornea / Q000378:metabolism* / Q000473:pathology; D003318:Corneal Opacity / Q000209:etiology* / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005901:Glaucoma / Q000209:etiology* / Q000235:genetics; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology; D010179:Pancreas / Q000378:metabolism; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016337:RNA, Catalytic / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism*; D027982:Sodium-Bicarbonate Symporters; D014634:Valinomycin / Q000494:pharmacology
D001639:Bicarbonates; D002352:Carrier Proteins; D002712:Chlorides; D005136:Eye Proteins; D020033:Protein Isoforms; D016337:RNA, Catalytic; D012333:RNA, Messenger; D027982:Sodium-Bicarbonate Symporters; C432166:hammerhead ribozyme RZ-NBC; D014634:Valinomycin; D000584:Amiloride; D012964:Sodium; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid