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Exp Eye Res. 2013 Mar;108:59-67. doi: 10.1016/j.exer.2012.12.008. Epub 2012 Dec 26.

A reduced zinc diet or zinc transporter 3 knockout attenuate light induced zinc accumulation and retinal degeneration.

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Department of Ophthalmology and The Neuroscience Center of Excellence, LSU Health Sciences Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA.


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.

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