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

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 4 h. We light exposed (70 kLux of white light for 50 h) 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 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 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.

► Zn2+ accrual and NAD+ loss induce PRC toxicity which is reduced by P, N, and NAD+. ► A Zn2+ reduced diet reduced photoreceptor Zn2+ staining and degeneration after LD. ► ZnT3-KO mice have less Zn2+ staining and photoreceptor and RPE cell death after LD. ► NAD+ levels after the LD were not significantly reduced in ZnT3-KO mice. ► RPE65-KO mice are resistant to LD, and have no photoreceptor Zn2+ staining after LD.