Abstract
BackgroundVision is initiated by phototransduction in the outer retina by photoreceptors, whose high metabolic rate generates large CO2 loads. Inner retina cells then process the visual signal and CO2. The anion exchanger 3 gene (AE3/Slc4a3) encodes full-length AE3 (AE3fl) and cardiac AE3 (AE3c) isoforms, catalyzing plasma membrane Cl−/HCO3 − exchange in Müller (AE3fl) and horizontal (AE3c) cells. AE3 thus maintains acid-balance by removing photoreceptor-generated CO2 waste.Methodology/Principal FindingsWe report that Slc4a3−/− null mice have inner retina defects (electroretinogram b-wave reduction, optic nerve and retinal vessel anomalies). These pathologic features are common to most human vitreoretinal degenerations. Immunobloting analysis revealed that Na+/HCO3 − co-transporter (NBC1), and carbonic anhydrase II and CAXIV, protein expression were elevated in Slc4a3 −/− mouse retinas, suggesting compensation for loss of AE3. TUNEL staining showed increased numbers of apoptotic nuclei from 4–6 months of age, in Slc4a3 −/− mice, indicating late onset photoreceptor death.Conclusions/SignificanceIdentification of Slc4a3 as underlying a previously unrecognized cause of blindness suggests this gene as a new candidate for a subset of hereditary vitreoretinal retinal degeneration.
Highlights
The human retina has extremely high rates of aerobic metabolism and oxygen consumption, which generates large CO2 loads [1]
We report that mice with homozygous disruption of Slc4a3 present with inner retinal defects and late onset photoreceptor death, which are the pathologic features of most human hereditary vitreoretinal degenerations (HVD) [11]
We have demonstrated that the apoptotic cascade is initiated as a result of absence of AE3-mediated HCO32 fluxes
Summary
The human retina has extremely high rates of aerobic metabolism and oxygen consumption, which generates large CO2 loads [1]. Efficient elimination of the considerable CO2 and H+ load produced by photoreceptor activity is necessary to maintain intracellular (pHi) and extracellular (pHo) pH homeostasis. Activity of plasma membrane acid and base transporters in neurons and glial cells of the retina regulate those changes. Vision is initiated by phototransduction in the outer retina by photoreceptors, whose high metabolic rate generates large CO2 loads. We report that Slc4a32/2 null mice have inner retina defects (electroretinogram b-wave reduction, optic nerve and retinal vessel anomalies). These pathologic features are common to most human vitreoretinal degenerations. Identification of Slc4a3 as underlying a previously unrecognized cause of blindness suggests this gene as a new candidate for a subset of hereditary vitreoretinal retinal degeneration
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