title: A reduced zinc diet or zinc transporter 3 knockout attenuate light induced zinc accumulation and retinal degeneration.
abstract: Our previous study on retinal light exposure suggests the involvement of zinc (Zn(2+)) toxicity in the death of RPE and photoreceptors (LD) which could be attenuated by pyruvate and nicotinamide, perhaps through restoration of NAD(+) levels. In the present study, we examined Zn(2+) toxicity, and the effects of NAD(+) restoration in primary retinal cultures. We then reduced Zn(2+) levels in rodents by reducing Zn(2+) levels in the diet, or by genetics and measured LD. Sprague Dawley albino rats were fed 2, or 61 mg Zn(2+)/kg of diet for 3 weeks, and exposed to 18 kLux of white light for 4 h. We light exposed (70 kLux of white light for 50 h) Zn(2+) transporter 3 knockout (ZnT3-KO, no synaptic Zn(2+)), or RPE65 knockout mice (RPE65-KO, lack rhodopsin cycling), or C57/BI6/J controls and determined light damage and Zn(2+) staining. Retinal Zn(2+) staining was examined at 1 h and 4 h after light exposure. Retinas were examined after 7 d by optical coherence tomography and histology. After LD, rats fed the reduced Zn(2+) diet showed less photoreceptor Zn(2+) staining and degeneration compared to a normal Zn(2+) diet. Similarly, ZnT3-KO and RPE65-KO mice showed less Zn(2+) staining, NAD(+) loss, and RPE or photoreceptor death than C57/BI6/J control mice. Dietary or ZnT3-dependent Zn(2+) stores, and intracellular Zn(2+) release from rhodopsin recycling are suggested to be involved in light-induced retinal degeneration. These results implicate novel rhodopsin-mediated mechanisms and therapeutic targets for LD. Our companion manuscript demonstrates that pharmacologic, circadian, or genetic manipulations which maintain NAD(+) levels reduce LD.
authors.affiliation: Department of Ophthalmology and The Neuroscience Center of Excellence, LSU Health Sciences Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA. sbai@lsuhsc.edu
authors.forename: Shi
authors.initials: S
authors.lastname: Bai
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Sheline
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Christian T
authors.initials: CT
authors.lastname: Sheline
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004032:Diet; D004195:Disease Models, Animal; D008027:Light / Q000009:adverse effects*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012162:Retinal Degeneration / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012243:Rhodopsin / Q000378:metabolism; D013997:Time Factors; D041623:Tomography, Optical Coherence; D015032:Zinc / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D019745:cis-trans-Isomerases / Q000172:deficiency / Q000235:genetics; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009243:NAD; D012243:Rhodopsin; D015032:Zinc; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C491177:Slc30a3 protein, mouse