title: Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis.
abstract: 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.
authors: Department of Ophthalmology, Faculty of Medicine, Tokyo University, Bunkyo-ku, Tokyo, Japan.
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authors: Usui
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authors: Hara
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authors: Satoh
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authors: Moriyama
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authors: Kagaya
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authors: Endou
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authors: Fujita
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authors: Seki
mesh_terms: 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
chemical_list: 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