Our previous study on retinal light exposure suggests the involvement of zinc (Zn2+) 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 Zn2+ toxicity, and the effects of NAD+ restoration in primary retinal cultures. We then reduced Zn2+ levels in rodents by reducing Zn2+ levels in the diet, or by genetics and measured LD. Sprague Dawley albino rats were fed 2, or 61 mg Zn2+/kg of diet for 3 weeks, and exposed to 18 kLux of white light for 4h. We light exposed (70 kLux of white light for 50h) Zn2+ transporter 3 knockout (ZnT3-KO, no synaptic Zn2+), or RPE65 knockout mice (RPE65-KO, lack rhodopsin cycling), or C57/BI6/J controls and determined light damage and Zn2+ staining. Retinal Zn2+ staining was examined at 1h and 4h after light exposure. Retinas were examined after 7d by optical coherence tomography and histology. After LD, rats fed the reduced Zn2+ diet showed less photoreceptor Zn2+ staining and degeneration compared to a normal Zn2+ diet. Similarly, ZnT3-KO and RPE65-KO mice showed less Zn2+ staining, NAD+ loss, and RPE or photoreceptor death than C57/BI6/J control mice. Dietary or ZnT3-dependent Zn2+ stores, and intracellular Zn2+ 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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