The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells
IntroductionAge-related macular degeneration (AMD), a degenerative disease of the macula, is caused by an interplay of diverse risk factors (genetic predisposition, age and lifestyle habits). One of the main genetic risks includes the Y402H polymorphism in complement Factor H (FH), an inhibitor of c...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| author | Angela Armento Inga Sonntag Ana-Cristina Almansa-Garcia Merve Sen Sylvia Bolz Blanca Arango-Gonzalez Ellen Kilger Ruchi Sharma Kapil Bharti Rosario Fernandez-Godino Berta de la Cerda Simon J. Clark Simon J. Clark Simon J. Clark Marius Ueffing |
| author_facet | Angela Armento Inga Sonntag Ana-Cristina Almansa-Garcia Merve Sen Sylvia Bolz Blanca Arango-Gonzalez Ellen Kilger Ruchi Sharma Kapil Bharti Rosario Fernandez-Godino Berta de la Cerda Simon J. Clark Simon J. Clark Simon J. Clark Marius Ueffing |
| author_sort | Angela Armento |
| collection | DOAJ |
| description | IntroductionAge-related macular degeneration (AMD), a degenerative disease of the macula, is caused by an interplay of diverse risk factors (genetic predisposition, age and lifestyle habits). One of the main genetic risks includes the Y402H polymorphism in complement Factor H (FH), an inhibitor of complement system activation. There has been, and continues to be, much discussion around the functional consequences of this Y402H polymorphism, whether the soluble FH protein confers its risk association, or if the cells expressing the protein themselves are affected by the genetic alteration. In our study, we examined the cell characteristics of the retinal pigment epithelium (RPE) cells, which play a major role in retinal homeostasis and stability and which are synonymously linked to AMD.MethodsHere, we employ RPE cells derived from induced pluripotent stem cells (iPSC) generated from donors, carrying either homozygous 402Y (low risk) or 402H (high risk) variants of the CFH gene. RPE cells were treated with Hydroquinone (HQ), a component of cigarette smoke, to induce oxidative damage. ResultsIntriguingly, RPE cells carrying high genetic risk proved more vulnerable to oxidative insult when exposed to HQ, as demonstrated by increased cytotoxicity and caspase activation, compared to the low-risk RPE cells. The exposure of RPE cells to RPE conditioned medium, normal human serum (NHS) and inactivated NHS (iNHS) had minimal impact on cell cytotoxicity and caspase activation, nor did the presence of purified soluble FH rescue the observed effects. Considering the known connection of oxidative stress to proteotoxic stress and degrading processes, we investigated the unfolded protein response (UPR) and autophagy. When exposed to HQ, RPE cells showed an increase in autophagy markers; however, iPSC-RPE cells carrying high genetic risk showed an overall reduced autophagic flux. DiscussionOur findings suggest that the degree of cellular susceptibility to oxidative stress is not conferred by soluble FH protein and other complement sources, but intercellularly because of the corresponding genetic risk predisposition. Our data support the hypothesis that RPE cells carrying high genetic risk are less resilient to oxidative stress. |
| format | Article |
| id | doaj-art-1883389e2631441b97e22ec07b95045b |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-02-01 |
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| series | Frontiers in Immunology |
| spelling | doaj-art-1883389e2631441b97e22ec07b95045b2025-02-06T07:10:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15270181527018The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cellsAngela Armento0Inga Sonntag1Ana-Cristina Almansa-Garcia2Merve Sen3Sylvia Bolz4Blanca Arango-Gonzalez5Ellen Kilger6Ruchi Sharma7Kapil Bharti8Rosario Fernandez-Godino9Berta de la Cerda10Simon J. Clark11Simon J. Clark12Simon J. Clark13Marius Ueffing14Department for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyDepartment for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyDepartment for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyDepartment for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyDepartment for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyDepartment for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyDepartment for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyOcular Stem Cells and Translational Research (OSCTR) Section, Ophthalmic Genetic and Visual Function Branch (OGVFB), National Eye Institute, National Institutes of Health, Bethesda, MD, United StatesOcular Stem Cells and Translational Research (OSCTR) Section, Ophthalmic Genetic and Visual Function Branch (OGVFB), National Eye Institute, National Institutes of Health, Bethesda, MD, United StatesScreening and Target Validation, Fundacion MEDINA, Granada, SpainRetinal Neurodegeneration and Advanced Therapies, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, SpainDepartment for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyUniversity Eye Clinic, Eberhard Karls University of Tübingen, Tübingen, GermanyLydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, United KingdomDepartment for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, GermanyIntroductionAge-related macular degeneration (AMD), a degenerative disease of the macula, is caused by an interplay of diverse risk factors (genetic predisposition, age and lifestyle habits). One of the main genetic risks includes the Y402H polymorphism in complement Factor H (FH), an inhibitor of complement system activation. There has been, and continues to be, much discussion around the functional consequences of this Y402H polymorphism, whether the soluble FH protein confers its risk association, or if the cells expressing the protein themselves are affected by the genetic alteration. In our study, we examined the cell characteristics of the retinal pigment epithelium (RPE) cells, which play a major role in retinal homeostasis and stability and which are synonymously linked to AMD.MethodsHere, we employ RPE cells derived from induced pluripotent stem cells (iPSC) generated from donors, carrying either homozygous 402Y (low risk) or 402H (high risk) variants of the CFH gene. RPE cells were treated with Hydroquinone (HQ), a component of cigarette smoke, to induce oxidative damage. ResultsIntriguingly, RPE cells carrying high genetic risk proved more vulnerable to oxidative insult when exposed to HQ, as demonstrated by increased cytotoxicity and caspase activation, compared to the low-risk RPE cells. The exposure of RPE cells to RPE conditioned medium, normal human serum (NHS) and inactivated NHS (iNHS) had minimal impact on cell cytotoxicity and caspase activation, nor did the presence of purified soluble FH rescue the observed effects. Considering the known connection of oxidative stress to proteotoxic stress and degrading processes, we investigated the unfolded protein response (UPR) and autophagy. When exposed to HQ, RPE cells showed an increase in autophagy markers; however, iPSC-RPE cells carrying high genetic risk showed an overall reduced autophagic flux. DiscussionOur findings suggest that the degree of cellular susceptibility to oxidative stress is not conferred by soluble FH protein and other complement sources, but intercellularly because of the corresponding genetic risk predisposition. Our data support the hypothesis that RPE cells carrying high genetic risk are less resilient to oxidative stress.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527018/fullage-related macular degeneration (AMD)complement factor H (CFH)retinal pigment epithelium (RPE) cellsoxidative stressautophagy |
| spellingShingle | Angela Armento Inga Sonntag Ana-Cristina Almansa-Garcia Merve Sen Sylvia Bolz Blanca Arango-Gonzalez Ellen Kilger Ruchi Sharma Kapil Bharti Rosario Fernandez-Godino Berta de la Cerda Simon J. Clark Simon J. Clark Simon J. Clark Marius Ueffing The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells Frontiers in Immunology age-related macular degeneration (AMD) complement factor H (CFH) retinal pigment epithelium (RPE) cells oxidative stress autophagy |
| title | The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells |
| title_full | The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells |
| title_fullStr | The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells |
| title_full_unstemmed | The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells |
| title_short | The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells |
| title_sort | amd associated genetic polymorphism cfh y402h confers vulnerability to hydroquinone induced stress in ipsc rpe cells |
| topic | age-related macular degeneration (AMD) complement factor H (CFH) retinal pigment epithelium (RPE) cells oxidative stress autophagy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527018/full |
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