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Apical-To-Basolateral Transcytosis of Photoreceptor Outer Segments Induced by Lipid Peroxidation Products in Human Retinal Pigment Epithelial Cells

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Apical-To-Basolateral Transcytosis of Photoreceptor Outer Segments Induced by Lipid Peroxidation Products in Human Retinal Pigment Epithelial Cells Retinal Cell Biology Apical-to-Basolateral Transcytosis of Photoreceptor Outer Segments Induced by Lipid Peroxidation Products in Human Retinal Pigment Epithelial Cells Tim U. Krohne,1 Frank G. Holz,1 and Ju¨rgen Kopitz2 PURPOSE. Progressive accumulation of extracellular material at posit formation and drusen biogenesis in AMD. (Invest Oph- the basolateral side of the retinal pigment epithelium (RPE) is thalmol Vis Sci. 2010;51:553–560) DOI:10.1167/iovs.09-3755 a key event in the pathogenesis of age-related macular degen- eration (AMD). The authors previously demonstrated that mod- rogressive deposition of extracellular material between the ifications with lipid peroxidation products, such as 4-hy- basolateral side of the retinal pigment epithelium (RPE) droxynonenal (HNE) and malondialdehyde (MDA), stabilize P and adjacent Bruch’s membrane is a hallmark of early-stage photoreceptor outer segment (POS) proteins against lysosomal age-related macular degeneration (AMD).1,2 Among the various degradation. Herein, they tested RPE cells for the basolateral histologically and clinically distinguishable manifestations of release of undegraded modified POS proteins. sub-RPE deposits, basal linear deposits (BLinD) and soft drusen METHODS. Polarized cultures of the human RPE cell line are recognized as specific for AMD.3,4 Both BLinD and soft ARPE-19 on permeable membranes were incubated with io- drusen represent accumulations of material described as mem- dine-125–labeled POS on the apical side. After 24 hours, radio- branous debris5 between the RPE basement membrane and the activity was quantified in apical medium, cell lysates, and inner collagenous layer of Bruch’s membrane and are, there- basolateral medium after separation of undegraded proteins by fore, considered diffuse and focal manifestations, respectively, precipitation. Protein composition of basolaterally released of the same lesion.1,3,6 The prognostic relevance of drusen size POS material was analyzed by two-dimensional gel electro- and number for the progression of AMD has been well estab- phoresis. C3a- and SC5b-9-specific enzyme-linked immunosor- lished.7–9 bent assays were used to assess complement activation by When Heinrich Mu¨ller initially coined the term drusen in modified POS. 1856, he already suggested that material deposition by the retinal pigment epithelium might contribute to their develop- RESULTS. The amount of phagocytic uptake was similar for 10 native and modified POS. Unmodified POS proteins were al- ment. Today, more than one and a half centuries later, the most completely (98.1%) degraded, whereas degradation of mechanisms of sub-RPE deposit formation are still not com- HNE- and MDA-modified POS proteins was significantly re- pletely resolved. However, proteomic studies revealed that duced (47.2%; 56.5%). Undegraded POS proteins accumulated drusen and aged Bruch’s membranes contain proteins that are intracellularly (14.2%; 12.1%) and were trafficked through the covalently modified by products of lipid peroxidation, and these modifications were more abundant in AMD eyes than in cells to be released into the basolateral medium (38.5%; 11 31.5%). Protein composition of basolaterally released material age-matched control eyes. Lipid peroxidation is a mechanism of oxidative damage that predominantly affects tissues, such as matched the original POS preparations. Protein modifications the outer retina, that are exposed to high levels of oxidative or did not confer increased complement-activating capacity to photooxidative stress and are highly enriched in polyunsatu- POS material. rated fatty acids (PUFAs). In lipid peroxidation, oxygen-derived CONCLUSIONS. Inhibition of lysosomal degradation by lipid per- free radicals interact with PUFA double bounds, resulting in oxidation-related protein modifications induces apical-to-baso- cleavage into a variety of highly reactive aldehydes, such as lateral transcytosis of undegraded POS proteins by human RPE malondialdehyde (MDA) and 4-hydroxynonenal (HNE).12 Once cells in vitro. This mechanism may contribute to sub-RPE de- formed, these lipid peroxidation products rapidly attach co- valently to nearby proteins by forming adducts predominantly with cysteine, lysine, and histidine residues, a process that may interfere with protein functionality.12 Furthermore, modified From the 1Department of Ophthalmology, University of Bonn, Bonn, Germany; and the 2Department of Molecular Pathology, Univer- proteins, also referred to as advanced lipid peroxidation end- products (ALE), are prone to aggregation by cross-linking of the sity of Heidelberg, Heidelberg, Germany. 12 Supported by the German Research Foundation (DFG) Grant KR adducts. By these mechanisms, lipid peroxidation products 2863/6-1 (TUK); DFG Priority Program “Age-related macular degener- cause severe damage to cellular proteins and other macromol- ation” (SPP 1088) Grant HO 1926/2-1 (JK, FGH); the University of Bonn ecules and thus impair cellular functions and survival. BONFOR Program Gerok Fellowship (TUK); the German Ophthalmo- We previously detected modifications with MDA and HNE logical Society Alcon Retina Scholarship (TUK); and the Dr. Eberhard on proteins isolated from RPE-derived lipofuscin, thus demon- und Hilde Ru¨diger Foundation (TUK). strating the occurrence of these substances in the RPE lysoso- Submitted for publication March 23, 2009; revised June 13, 2009; mal compartment and suggesting their contribution to lysoso- accepted August 6, 2009. 13 Disclosure: T.U. Krohne, None; F.G. Holz, None; J. Kopitz, mal dysfunction and lipofuscinogenesis. Indeed, we None observed that modifications of photoreceptor outer segment Corresponding author: Tim U. Krohne, Department of Ophthal- (POS) proteins with MDA and HNE significantly reduced their 14 mology, University of Bonn, Ernst-Abbe-Strasse 2, D-53127 Bonn, Ger- degradation by RPE cells in vitro. After normal phagocytic many; [email protected]. uptake, modified POS proteins exhibited increased stability Investigative Ophthalmology & Visual Science, January 2010, Vol. 51, No. 1 Copyright © Association for Research in Vision and Ophthalmology 553 Downloaded from iovs.arvojournals.org on 09/27/2021 554 Krohne et al. IOVS, January 2010, Vol. 51, No. 1 against the proteolytic attack by lysosomal enzymes, resulting Paracellular Permeability Assays in their intracellular accumulation and long-term storage. In the present study, we further analyzed the processing of modified To assess RPE cell monolayer integrity, we measured transepithelial POS by human RPE cells in vitro and tested whether undegrad- electrical resistance (TEER) across cell monolayers using a volt-ohm- ⍀ 2 able POS components are disposed into the sub-RPE space, a meter (Millicell-ERS; Millipore, Billerica, MA). TEER ( cm ) was calcu- ⍀ 2 process that may contribute to local immune processes and lated as electrical resistance ( ) multiplied by cell culture area (cm ). sub-RPE deposit formation in vivo. Values derived from laminin-coated membranes without cells were subtracted as background. RPE monolayers in our culture system reached TEER values of 63 ⍀cm2 (Ϯ7) after 7 days of culture. MATERIALS AND METHODS Paracellular permeability was analyzed by means of marker dye leakage. We used FITC-dextran (molecular weight, 40 kDa; Sigma- RPE Cell Culture Aldrich) as the marker substance because it was previously shown not The human, spontaneously stable RPE cell line ARPE-19 (ATCC CRL- to be transported transcellularly by RPE cells.17 FITC-dextran was 2302) was obtained from American Type Culture Collection (Rockville, added to the medium on the apical cell side of membrane-cultured RPE MD) and was maintained in a 1:1 mixture of Dulbecco’s modified cell monolayers at a concentration of 100 ␮M. After 2 hours on a Eagle’s medium (DMEM) and Ham’s F-12 medium (PAA Laboratories, horizontal shaker (40 rpm) in a cell culture incubator, FITC-specific Co¨lbe, Germany) containing 2.5 mM L-glutamine, 0.5 mM sodium fluorescence in the basolateral medium was quantified using a micro- pyruvate, and 17.5 mM D-glucose and supplemented with 100 U/mL plate reader (excitation wavelength, 485 nm; detection wavelength, penicillin, 100 ␮g/mL streptomycin, and 10% heat-inactivated fetal 528 nm). Apparent permeability coefficient (Papp; cm/s) was calculated bovine serum (PAA Laboratories) at 37°C in a humidified atmosphere as marker dye flux across the cell monolayer (␮g/s) divided by cell 2 of 5% CO2 in air. Permeable polyester membrane cell culture inserts culture area (cm ) and initial marker dye concentration in the apical (Transwell-Clear, diameter 12 mm, pore size 0.4 ␮m; Corning, Lowell, medium (␮g/cm3). Experiments were performed in triplicate, and MA) were coated with 2 ␮g/cm2 laminin (Sigma-Aldrich, Munich, results are presented as mean (ϮSD). Germany) for 2 hours at 37°C according to the manufacturer’s recom- mendation. Postconfluent stationary cells were trypsinized, seeded on Electron Microscopy Studies the membranes at a density of 1.66 ϫ 105/cm2 as previously de- For transmission electron microscopy (TEM) analysis, cells were fixed scribed,15,16 and cultured for 7 additional days before use in experi- with Karnovsky’s solution in PBS (pH 7.3), postfixed in 1% OsO , ments. The upper and lower compartments of the cell culture inserts 4 dehydrated in ethanol, and embedded (Durcupan ACM Fluka; Sigma- were filled with 500 ␮L and 1500 ␮L culture medium, respectively, to Aldrich). Ultrathin sections were stained with uranyl acetate and lead achieve hydrostatic equilibrium. Under these
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