title: Cadmium-induced apoptotic death of human retinal pigment epithelial cells is mediated by MAPK pathway.
abstract: Cadmium (Cd), released from cigarette smoke and metal industrial activities, is known to accumulate in human body organs including retina and is particularly higher in retinal tissues of age-related macular degeneration (AMD) eyes compared to non-AMD eyes. We have determined the cytotoxic effects of Cd on human retinal pigment epithelial (RPE) cells. Upon Cd treatment, there was a dose- and time-dependent decline in ARPE-19 cell viability as well as early apoptotic changes such as altered mitochondrial membrane potential (MMP) and Cytochrome C release in cytosol. Depletion of GSH by buthionine-[S,R]-sulfoximine (BSO) resulted in increased Cd toxicity in ARPE-19 cells. Cadmium also caused reactive oxygen species (ROS) generation and activation of mitogen-activated protein kinases (MAPKs) pathway including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (Erk1/2), and p38 in ARPE-19 cells. Antioxidants such as N-acetylcysteine (NAC) significantly reduced Cd-induced toxicity. These results indicate that elevated ROS-induced activation of the MAPK signaling pathway could be associated with Cd-induced RPE cell apoptosis, one of the major contributing factors in AMD. The toxic effects of Cd on ARPE-19 cells indicate that environmental heavy metals such as Cd could be important potential factors in RPE cells death associated retinal diseases particularly related to smoking.
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Nilesh M
authors.initials: NM
authors.lastname: Kalariya
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Wills
authors.forename: Kota V
authors.initials: KV
authors.lastname: Ramana
authors.forename: Satish K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Frederik J G M
authors.initials: FJ
authors.lastname: van Kuijk
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D019256:Cadmium Chloride / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; D019256:Cadmium Chloride; D000111:Acetylcysteine