title: Digoxin-induced retinal degeneration depends on rhodopsin.
abstract: Na,K-ATPases are energy consuming ion pumps that are required for maintaining ion homeostasis in most cells. In the retina, Na,K-ATPases are especially important to sustain the dark current in photoreceptor cells needed for rapid hyperpolarization of rods and cones in light. Cardiac glycosides like digoxin inhibit the activity of Na,K-ATPases by targeting their catalytic alpha subunits. This leads to a disturbed ion balance, which can affect cellular function and survival. Here we show that the treatment of wild-type mice with digoxin leads to severe retinal degeneration and loss of vision. Digoxin induced cell death specifically in photoreceptor cells with no or only minor effects in other retinal cell types. Photoreceptor-specific cytotoxicity depended on the presence of bleachable rhodopsin. Photoreceptors of Rpe65 knockouts, which have no measurable rhodopsin and photoreceptors of Rpe65R91Wmice that have <10% of the rhodopsin found in retinas of wild-type mice were not sensitive to digoxin treatment. Similarly, cones in the all-cone retina of Nrl knockout mice were also not affected. Digoxin induced expression of several genes involved in stress signaling and inflammation. It also activated proteins such as ERK1/2, AKT, STAT1, STAT3 and CASP1 during a period of up to 10 days after treatment. Activation of signaling genes and proteins, as well as the dependency on bleachable rhodopsin resembles mechanisms of light-induced photoreceptor degeneration. Digoxin-mediated photoreceptor cell death may thus be used as an inducible model system to study molecular mechanisms of retinal degeneration.
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Landfried
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.
authors.forename: Marijana
authors.initials: M
authors.lastname: Samardzija
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.|Neuroscience Center Zürich (ZNZ), University of Zürich, Zürich, Switzerland.
authors.forename: Maya
authors.initials: M
authors.lastname: Barben
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.|Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schori
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.|Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Klee
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Storti
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.|Neuroscience Center Zürich (ZNZ), University of Zürich, Zürich, Switzerland.|Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004077:Digoxin / Q000494:pharmacology*; D005136:Eye Proteins / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012160:Retina / Q000187:drug effects* / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D012162:Retinal Degeneration / Q000139:chemically induced* / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D012243:Rhodopsin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D014785:Vision, Ocular / Q000187:drug effects; D019745:cis-trans-Isomerases / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D004077:Digoxin; D012243:Rhodopsin; D019745:cis-trans-Isomerases; D000254:Sodium-Potassium-Exchanging ATPase