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1From the Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; and the 2Departments of Ophthalmology and 3Molecular and Cellular Biology, University of California, Davis, Davis, California.
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Abstract |
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METHODS. Total RNA was prepared from human donor eyes and from ARPE-19 cell cultures. Expression of MCT transcripts was evaluated by RT-PCR amplification. Expression of MCT proteins in human RPE and ARPE-19 cells was evaluated by immunolocalization and Western blot analysis with isoform-specific anti-peptide antibodies.
RESULTS. The expression of MCTs in human RPE was investigated by immunofluorescence analysis on frozen sections of human donor eyes. MCT1 antibody labeled the apical membrane of the RPE intensely, whereas MCT3 labeling was restricted to the basolateral membrane. MCT4 was detected in the neural retina but not in the RPE. ARPE-19 cells constitutively expressed MCT1 and MCT4 mRNAs. Expression of MCT3 mRNA increased over time as ARPE-19 cells established a differentiated phenotype. Western blot analysis revealed that ARPE-19 cells expressed high levels of MCT1 and MCT4 but very little MCT3 protein. Sections of differentiated ARPE-19 cells were labeled with MCT1, MCT4, and glucose transporter-1 antibodies. MCT1 was polarized to the apical membrane and MCT4 to the basolateral membrane, whereas GLUT1 was expressed in both membrane domains. CD147, which is necessary for targeting MCTs to the plasma membrane, was detected in the apical and basolateral membranes of human RPE in situ and ARPE-19 cells.
CONCLUSIONS. These studies demonstrate for the first time that human RPE expresses two proton-coupled monocarboxylate transporters: MCT1 in the apical membrane and MCT3 in the basolateral membrane. The coordinated activities of these two transporters could facilitate the flux of lactate from the retina to the choroid. ARPE-19 cells express two MCT isoforms, polarized to different membrane domains: MCT1 to the apical membrane and MCT4 to the basolateral membrane. The polarized expression of MCTs in ARPE-19 demonstrates that these cells retain the cellular machinery necessary for transepithelial transport of lactate.
Substances that are produced and used in large quantity, such as glucose, amino acids, and lactate are moved into and out of the retina by facilitated diffusion. Glucose, the preferred energy substrate for the neural retina is transported from the choroidal vessels to the outer retina through GLUT1, which is present in both apical and basolateral membranes of the RPE.2 Most of the glucose transported into the outer retina is metabolized through aerobic glycolysis, resulting in the production of quantities of lactate.3 4 5 6
Transport of lactate, pyruvate, and ketone bodies across the plasma membrane occurs in virtually all eukaryotic cells through a family of proton-coupled monocarboxylate transporters (MCTs).7 Eight members of this family have been cloned in humans and their homology, on the basis of primary structure, varies between 25% to 60% identity. Analysis of the derived amino acid sequences of MCTs has revealed that the cDNAs encode proteins with 12 membrane-spanning domains connected by short hydrophilic loops with a long cytoplasmic loop separating the sixth and seventh transmembrane (TM) segments. The amino and carboxyl termini are cytoplasmic. In accord with other transporter families, MCT isoforms differ in temporal and spatial patterns of expression. MCT1 is the most widely distributed isoform and is expressed in most mammalian tissues and in most cell lines.8 MCT3, originally cloned from a chicken RPE expression library is preferentially expressed in the RPE.9 10 MCT4 is a low-affinity lactate transporter that transports lactate out of glycolytic cells.11 Western blot and immunohistochemical analyses have shown that MCT4 is most abundant in fast-twitch muscle12 and neural retina.13
In previous studies we reported that two lactate transporters are expressed in both rat and mouse RPE: MCT1 in the apical membrane and MCT3 in the basolateral membrane.10 14 The coordinated activity of two transporters could provide a mechanism for transporting lactate out of the retina. In the present study, we examined the expression of MCTs in human RPE in situ and in ARPE-19 cells, a human RPE cell line. ARPE-19 cells have been used as a model system for studying differentiation, regulation of protein expression, and response of RPE to oxidative damage. We wanted to determine whether ARPE-19 cells properly express and polarize MCTs and their associated protein CD147.
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Materials and Methods |
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FRT cells, kindly provided by Enrique Rodriguez-Boulan (Dyson Institute of Ophthalmology, Cornell University Medical Center, New York, NY), were cultured in Coon’s modified Ham’s F-12 medium supplemented with 5% fetal bovine serum, 2 mM L-glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin. Cells were transfected with the full-coding sequence of human MCT3 cDNA cloned into the pTargeT vector (Promega, Madison, WI), with a transfection reagent (FuGENE 6; Roche Molecular Biochemicals, Indianapolis, IN) used according to the manufacturer’s procedures. Stably transfected cell lines were selected by growth in the antibiotic G418 (Stratagene, La Jolla, CA), and resistant colonies were isolated and propagated. Expression of MCT3 protein was demonstrated by immunoblot analysis and immunohistochemistry.
Preparation of Antibodies against Human MCT1 and -3
Anti-peptide antibodies were raised in rabbits against the carboxyl terminal peptides of MCT1, -3, and -4. This domain of the MCTs is not conserved between isoforms ensuring the production of isoform-specific antibodies. An anti-human MCT1 antibody was raised in rabbits against the C terminus of MCT1, residues 483-500: (C)SPDQKDTEGGPKEEESPV-COOH. The peptide antibody was produced and affinity purified by Zymed Laboratories (San Francisco, CA). An anti-human MCT3 antibody was raised in rabbits to the C-terminal peptide of human MCT3 residues (C)GEPTEPEIEARPRLAAAESV-COOH. The antibody was produced and affinity purified by Research Genetics (Huntsville, AL). MCT4 antibodies were raised against an 18-mer synthetic oligopeptide corresponding to the carboxyl terminal amino acids (KAEPEKNGEVVHTPETSV) of mouse MCT4 (Zymed Laboratories). This sequence is conserved between mouse and human MCT4. All antibodies were evaluated for specificity in our laboratory by Western blot and immunohistochemical analyses in the presence and absence of the appropriate peptide antigen.
GLUT1 antibody was a gift from Ian Simpson (Pennsylvania State University, Hershey, PA) and CD147 antibody (RDI-CD147-M6) was purchased from Research Diagnostics, Inc. (Flanders, NJ).
PCR Analysis
Total RNA was prepared from adult human donor eyes obtained from the Lions Eye Bank of Delaware (Philadelphia, PA) by using extraction reagent (TRIzol; Life Technologies Inc., Grand Island, NY), according to the manufacturer’s instructions. The protocol adhered to the provisions of the Declaration of Helsinki for the use of human tissue in research. After the retina was removed from the eyecup, 1 mL of extraction reagent was added to the eyecup to isolate RNA from the RPE-choroid. Total RNA was prepared from ARPE-19 cells by the same procedure.
Expression of MCT mRNAs in ARPE-19 cells and human RPE was determined using RT-PCR with isoform specific primers. First-strand cDNAs were prepared using 1.5 µg total RNA and 3'-rapid amplification of cDNA ends (RACE) adaptor Primer (3AP; 5'-ggc cac gcg tcg act agt act ttt ttt ttt ttt ttt t-3'; Life Technologies, Inc.). MCT isoforms were amplified using the following primer sets: MCT1 (forward primer, 5'-ttt ctt tgc ggc ttc cgt tgt tg-3', 993-1015, and reverse primer: 5'-tca att tac cct tca gcc cca tgg-3', 1529-1506); MCT3 (forward primer: 5'-tcg tgg gct tcg tgg aca tcg t-3', 881-902, and reverse primer: 5'-cag aca ccc agg gga tca act gga g-3', 1657-1633); and MCT4 (forward primer: 5'-ttt tgc tgc tgg gca act tct tct g-3', 1202-1226, and reverse primer: 5'-tca cgt tgt ctc gaa gca tgg gtt t-3', 1716-1692). The start codon (ATG) was referred to as 1 in positioning the primer. Forward primers to amplify the full coding sequence of each MCT were: MCT1 (-3 to -21) 5'-aaa atg cca cca gca gtt gga ggt-3'; MCT3 (-109 to -85), 5'-cag ttg tcc ttc aga ggg agc ctg c-3'; MCT4 (-23 to -3) 5'-agg cgg aac caa ccc tcc tgg-3'. Reverse primers were the same as just described. PCR products were separated on a 1.0% agarose gel. To confirm the expression of the exon two-splice variant, ARPE-19 cDNA was amplified with primers from exon 1b (5'-cag ttg tcc ttc aga ggg agc ctg-3') and exon 3 (5'-agc ggt cag gta gag ctc cag aag g-3'). PCR fragments were gel purified with an extraction kit (Qiaex II; Qiagen, Valencia, CA) and sequenced at the Nucleic Acid Facility in the Kimmel Cancer Institute at Thomas Jefferson University (Philadelphia, PA).
Western Blot Analysis
Cell lysates for Western blot analysis were prepared from ARPE-19 cells maintained for various lengths of time in culture. Cells were washed two times in PBS, then solubilized with ice-cold lysis buffer (1% Triton X-100, 10 mM imidazole, 100 mM KCl, 1 mM EDTA, 5 mM MgCl and protease inhibitors [Complete Mini; Roche]). Cell lysates were scraped from the dish, transferred into 1.5-mL tubes (Eppendorf, Fremont, CA), and triturated with a syringe. Samples were centrifuged at 15,000g for 15 minutes at 4°C and supernatants were removed and diluted with an equal volume of 2x SDS sample buffer containing 50 mM dithiothreitol. The protein concentration of the supernatants was determined using the bicinchoninic acid (BCA) reagent (Pierce, Rockford, IL). Cell lysates (15 µg protein per lane) were separated on 4% to 12% SDS-polyacrylamide gel and electrophoretically transferred to a membrane (Immobilon-P; Millipore, Bedford, MA). Membranes were incubated in primary and secondary antibodies by using a chemiluminescence detection system (Western Breeze; Invitrogen, San Diego, CA).
Cell and Tissue Preparation for Immunohistochemistry
Tissue from donor eyes was fixed in phosphate-buffered saline (PBS; pH 7.4) containing 4% paraformaldehyde, as previously described.16 ARPE-19 cells cultured for 120 days on 100-mm dishes were fixed in PBS containing 4% paraformaldehyde. After addition of the fixative, cells were gently lifted from the dish with a cell scraper and fixed for 1 hour at 4°C. The sheets of cells were washed in PBS and equilibrated in PBS containing increasing concentrations of sucrose: 10%, 20%, and 30%. Cells were then frozen in medium (Tissue Freezing Medium; Triangle Biomedical Science, Durham, NC). Cryosections (6–10 µm) were cut and mounted on glass microscope slides (Superfrost/Plus; Fisher Scientific, Pittsburgh, PA), and sections were air dried at room temperature and then stored at -80°C.
Immunofluorescence
Frozen sections of tissue or cells were blocked for 1 hour in PBS containing 5% bovine serum albumin (BSA) and 0.1% Tween 20 (pH 7.4) and then incubated for 1 hour with primary antibodies diluted in PBS containing 1% BSA and 0.1% Tween 20. The primary antibodies were detected using carboxymethylindocyanine (Cy3)-coupled secondary antibody (1:500; Jackson ImmunoResearch Laboratories, West Grove, PA) diluted in the same buffer as the primary antibodies. Sections were examined on a microscope (Microphot FX; Nikon, Tokyo, Japan) equipped with a digital camera (Optronics, Goleta, CA) and imaging software (Bioquant, Nashville, TN).
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ARPE-19 cells were cultured for 2 to 270 days to evaluate the expression of MCTs as a function of differentiation. RT-PCR was performed with a primer sets specific for MCT1, -3, and -4, as detailed in the Methods section. MCT1 and -4 mRNAs were constitutively expressed and were detected in cells cultured from 2 to 270 days (Fig. 3A) . In contrast, MCT3 mRNA was upregulated as a function of cell differentiation. MCT3 mRNA was detected at low levels in cells cultured for 30 days and increased as the cells differentiated. After 60 days, the level of MCT3 mRNA remained relatively constant.
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The distribution of MCT1 and -4 in ARPE-19 cells was examined by immunofluorescence localization. ARPE-19 cells cultured for 120 days were sectioned and stained with antibodies to MCT1, -3, and -4 and GLUT1. MCT1 was primarily detected in the apical membrane of ARPE-19 cells (Fig. 4) similar to human RPE in situ (Fig. 2B) . MCT4 antibody labeled the basolateral membranes of ARPE-19 cells. GLUT1 was detected in both membrane domains. ARPE-19 cells were not labeled with MCT3 antibody, suggesting that the expression was below the level of detection. This is consistent with the results from the Western blot analysis shown in Figure 3 .
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Discussion |
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MCT1 is the most widely expressed member of the MCT family. In human RPE, we found that MCT1 was abundantly expressed in the apical membrane of the RPE, in agreement with our previous studies in mouse and rat RPE.10 14 Whereas MCT1 was targeted to the apical membrane in RPE, in epithelia of the kidney, and small intestine, MCT1 was polarized to the basolateral membrane, adjacent to the capillary bed. Under normal physiological conditions, MCT1 transports lactate and ketone bodies into the cell to be metabolized through oxidative phosphorylation. However under hypoxic or ischemic conditions, MCT1 transports lactate out of the cells. The apical polarization of MCT1 is consistent with the observation that the RPE transports lactate from the subretinal space to the choroid, as discussed later.
Whereas MCT1 is widely expressed, MCT3 is preferentially expressed in the RPE.14 20 MCT3 labeling was restricted to the basolateral membrane of human RPE in situ. Labeling was not found in the neural retina or in other ocular tissues. Previously, we reported that MCT3 mRNA was expressed in human RPE but not in the neural retina.19 The MCT3 gene maps to chromosome 22 in location q12.3-13.2,19 the same loci as the TIMP3 gene. Mutations in the MCT3 gene have not been linked to retinal disease; however, alterations in the expression or targeting of MCT3 would be expected to have a severe impact on the chemical composition of the subretinal space and on photoreceptor function.
One of the critical functions of the RPE is to regulate the transport of nutrients into and out of the retina. The glucose transporter, GLUT1 is present in both the apical and basolateral membranes of the RPE facilitating the transepithelial movement of glucose from the choroid to the retina (Fig. 2F) . In the retina, 80% of the glucose is metabolized through aerobic glycolysis, resulting in the production of substantial quantities of lactate. The lactate produced is used by photoreceptor cells to fuel oxidative phosphorylation,21 and excess lactate produced is transported to the choroid by the RPE.22 The presence of MCT1 on the apical membrane and MCT3 on the basolateral membrane of the RPE identifies two proteins acting in concert that can mediate the transepithelial transfer of H+-lactate between the subretinal space and the systemic blood system. For L-lactate, Kms for MCT1 and -4 measured in an oocyte expression system are approximately 4 and 30 mM, respectively.11 The Km for chick MCT3 has been determined to be approximately 5.8 mM at pH 7.0.23 Lactate concentration in the subretinal space is estimated to be between 7 and 13 mM24 25 26 and may fluctuate during visual activity.21 The cytosolic concentration of lactate is unknown, but blood plasma lactate levels are normally approximately 1 mM. The chemical gradient for lactate would therefore favor the downward flow of lactate from the subretinal space to the choroidal blood plasma. Similarly, lactate influx at the basal membrane would be impeded by a higher Km of MCT3 at the basal membrane exposed to serum at a neutral pH. It is not known how distinct MCT isoforms in the apical and basal membranes can affect rates of lactate flux at the two membranes. Different isoforms may provide the means for independent regulation of expression and modulation of function by accessory factors.
ARPE-19 is a human RPE cell line shown to retain many of the structural and physiological properties of RPE in vivo.15 These cells have been used as a model system for functional studies on RPE.27 28 29 30 In addition, it has been proposed that ARPE-19 cells may be a source for subretinal transplantation.31 Because transepithelial movement of nutrients is a critical function of the RPE, we examined the expression of MCTs in undifferentiated and differentiated ARPE-19 cells. We found that ARPE-19 cells expressed transcripts for three MCTs: MCT1, -3, and -4. MCT1 and -4 were constitutively expressed, whereas expression of MCT3 was differentiation dependent. Western blot analysis revealed that MCT1 and -4 proteins were abundantly expressed in both undifferentiated and differentiated RPE. Although ARPE-19 cells retained the ability to express MCT3 mRNA, very little protein was detected.
In vivo, MCT4 is expressed in both the RPE and neural retina early in development but is turned off in the RPE as the cells mature.13 In ARPE-19 cells the MCT4 mRNA expression remained constant and did not decrease as the cells differentiated. The continued expression of MCT4 protein in ARPE-19 cells could inhibit the accumulation of MCT3 protein.
Immunofluorescence analysis revealed that ARPE-19 cells retained the ability to differentially target nutrient transporters. MCT1 was primarily targeted to the apical membrane, as was observed in RPE in situ. MCT4 was targeted to the basolateral membrane. The results indicate that targeting of MCT1 to the apical membrane is an inherent property of the RPE cells and is not dependent on interactions between the RPE and the neural retina.
As was observed in situ, GLUT1 was detected in the apical and basolateral membranes of ARPE-19 cells. This was not due to an absence of polarity but instead demonstrates that these cells retained the cellular machinery necessary to target the membrane proteins appropriately. In other polarized epithelial cells in culture, such as FRT cells, GLUT1 was polarized to the basolateral membrane (data not shown). CD147, which is required for targeting MCTs to the plasma membrane, colocalized with MCT1 in the apical membrane and MCT4 in the basolateral membrane of ARPE-19 cells.
In summary, in our study human RPE expressed two MCTs that were targeted to different membrane domains: MCT1 was polarized to the apical membrane and MCT3 to the basolateral membrane. The coordinated activity of these transporters could regulate the transport of lactate from the retina to the choroid. ARPE-19 cells expressed the appropriate polarization of MCTs and GLUT1, demonstrating that these cells had the cellular machinery necessary for transepithelial transport of glucose and lactate.
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Acknowledgements |
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Footnotes |
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Submitted for publication March 21, 2002; revised August 27 and October 24, 2002; accepted November 4, 2002.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Nancy J. Philp, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA, 19107; nancy.philp{at}mail.tju.edu.
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