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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / pharmacology
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Acidosis, Renal Tubular / complications*
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Acidosis, Renal Tubular / genetics
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Amiloride / pharmacology
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Animals
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Bicarbonates / metabolism*
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Blotting, Western
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cataract / etiology*
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Cataract / genetics
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Cells, Cultured
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Chlorides / metabolism
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Cornea / metabolism*
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Cornea / pathology
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Corneal Opacity / etiology*
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Corneal Opacity / genetics
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Eye Proteins / genetics*
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Eye Proteins / metabolism
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Glaucoma / etiology*
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Glaucoma / genetics
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Humans
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Ion Transport / genetics
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Kidney Tubules, Proximal / metabolism
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Lens, Crystalline / metabolism*
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Lens, Crystalline / pathology
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Pancreas / metabolism
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Protein Isoforms / deficiency
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Protein Isoforms / genetics*
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Protein Isoforms / metabolism
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RNA, Catalytic / chemistry
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RNA, Catalytic / pharmacology
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RNA, Messenger / biosynthesis
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Rats
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Reverse Transcriptase Polymerase Chain Reaction
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Sodium / metabolism*
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Sodium-Bicarbonate Symporters
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Valinomycin / pharmacology
Substances
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Bicarbonates
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Carrier Proteins
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Chlorides
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Eye Proteins
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Protein Isoforms
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RNA, Catalytic
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RNA, Messenger
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Sodium-Bicarbonate Symporters
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hammerhead ribozyme RZ-NBC
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Valinomycin
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Amiloride
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Sodium
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid