title: Protective effects of retinoid x receptors on retina pigment epithelium cells.
abstract: Age-related macular degeneration (AMD) is among the main pathologies leading to blindness in adults and has currently no cure or effective treatment. Selective apoptosis of retina pigment epithelial (RPE) cells results in the progressive loss of photoreceptor neurons, with the consequent gradual vision loss. Oxidative stress plays an important role in this process. We have previously determined that activation of RXRs protects rat photoreceptor neurons from oxidative stress-induced apoptosis. In this study we investigated whether RXR ligands prevented apoptosis in an RPE cell line, D407 cells, exposed to hydrogen peroxide (H2O2). H2O2 induced apoptosis of D407 cells, promoting p65NFκB nuclear translocation, increasing Bax mRNA expression, activating caspase-3 and altering cell morphology. We show, for the first time, that HX630, a RXR pan-agonist, protected D407 cells from H2O2-induced apoptosis, preventing p65NFκB nuclear translocation, increasing Bclxl and PPARγ mRNA levels and simultaneously decreasing Bax mRNA levels and caspase-3 activation. Pretreatment with a RXR antagonist blocked HX630 protection. LG100754, which binds RXRs but only activates heterodimers and is an antagonist of RXR homodimers, also had a protective effect. In addition, only agonists known to bind to RXR/PPARγ were protective. As a whole, our results suggest that RXR activation protects RPE cells from oxidative stress-induced apoptosis and this protection might involve signaling through a heterodimeric receptor, such as RXR/PPARγ. These data also imply that RXR agonists might provide potential pharmacological tools for treating retina degenerative diseases.
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Victoria Belén
authors.initials: VB
authors.lastname: Ayala-Peña
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Pilotti
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Yanel
authors.initials: Y
authors.lastname: Volonté
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Nora P
authors.initials: NP
authors.lastname: Rotstein
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Politi
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina. Electronic address: olgerman@criba.edu.ar.
authors.forename: Olga Lorena
authors.initials: OL
authors.lastname: German
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001552:Benzazepines / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018613:Microscopy, Confocal; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D001552:Benzazepines; D001565:Benzoates; C422175:HX 630; D016877:Oxidants; D047495:PPAR gamma; D020011:Protective Agents; D047488:Retinoid X Receptors; D051996:Transcription Factor RelA; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D006861:Hydrogen Peroxide; D053148:Caspase 3
keywords: Hydrogen peroxide; Oxidative stress; Peroxisome proliferator-activated receptor; Retina pigment epithelium cells; Retinoid x receptors