Metabolic Acid Transport in Human Retinal Pigment Epithelium

dc.contributor.advisorWang, Nam Sen_US
dc.contributor.advisorMiller, Sheldon Sen_US
dc.contributor.authorAdijanto, Jeffreyen_US
dc.contributor.departmentChemical Engineeringen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.description.abstractAt the back of our eyes, photoreceptors capture light and convert it into electrical signals that we perceive in our brain as vision. Photoreceptor function is energy expensive, even more so than many other processes in the body. Furthermore, photoreceptor metabolism increases in the dark and releases more metabolic by-products (CO2, lactic acid, and water) into the photoreceptor extracellular space (SRS). The retinal pigment epithelium (RPE) maintains photoreceptor health by transporting these metabolic acids from the SRS to the choroidal blood supply. By using native and cultured fetal human RPE, we show that the apical membrane is significantly more permeable to CO2 than the basolateral membrane. This feature traps CO2 in the cell and drives carbonic anhydrase (CA)-mediated hydration of CO2 into HCO3, which is subsequently transported out of the basolateral membrane by a Na-linked HCO3 co-transporter (NBC). This process increases net steady-state fluid absorption, thus maintaining retinal adhesion to the RPE. Oxidative metabolism generates significantly more ATP than glycolysis, but photoreceptors derive 50% of their total ATP consumed from glycolysis due to the low oxygen level at the photoreceptor inner segment. Furthermore, lactic acid production and release into the SRS almost doubles in the dark. We show that the RPE transports lactic acid from the SRS via a proton-linked monocarboxylate transporter (MCT1), and this process activates pHi-regulatory mechanisms at the RPE apical membrane: Na/H exchanger (NHE) and Na-linked HCO3 transporters (NBC1 & NBC3). These mechanisms also facilitate MCT1-mediated lactic acid transport by preventing buildup of a proton-gradient across the RPE apical membrane. We show that an increase in SRS CO2 or lactic acid level causes RPE cell swelling. The RPE alleviates swell-induced osmotic stress by activating apical membrane K-channel (Kir 7.1) and basolateral membrane Cl -channel (ClC-2), which drives KCl (and fluid) out of the cell to decrease cell volume. In this study, we identified the cellular mechanisms in RPE that prevent acidosis and fluid accumulation in the SRS caused by increased photoreceptor metabolism in the dark. These homeostatic processes maintain the close anatomical relationship between photoreceptors and RPE, thus protecting photoreceptor health and preserving visual function.en_US
dc.subject.pqcontrolledBiology, Physiologyen_US
dc.subject.pqcontrolledHealth Sciences, Ophthalmologyen_US
dc.subject.pqcontrolledHealth Sciences, Pharmacologyen_US
dc.subject.pquncontrolledcarbonic anhydraseen_US
dc.subject.pquncontrolledintracellular pHen_US
dc.titleMetabolic Acid Transport in Human Retinal Pigment Epitheliumen_US


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