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 (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.

Meeting Zn Needs during Medaka Eye Development: Nanoscale Visualization of Retina by Expansion Microscopy

“…Previous studies have reported that Zn plays an important role in photoreceptor ischemia-mediated cell death, which can be diminished by pyruvate and nicotinamide, probably by restoring NAD + levels. 71 Bai et al 72 demonstrated that a reduced Zn 2+ diet decreased the Zn 2+ staining and degeneration of photoreceptors under intense visible light, and Zn 2+ staining and photoreceptor cell death were observed less in ZnT3-KO (no synaptic Zn 2+ ) mice. In this study, we also found that the OS was more sensitive to the toxicity of high Zn levels than the IS, which was associated with a higher content of Zn in the photoreceptor OS.…”

hZnT8 (Slc30a8) Transgenic Mice That Overexpress the R325W Polymorph Have Reduced Islet Zn2+ and Proinsulin Levels, Increased Glucose Tolerance After a High-Fat Diet, and Altered Levels of Pancreatic Zinc Binding Proteins

“…These transport proteins function as multimers (21). ZnT3 knockout mice do not load Zn 2+ in synaptic vesicles and therefore are resistant to neuronal injury after light damage, global ischemia, or hypoglycemia (22,23 and C.T.S. and L. Wei, unpublished data).…”

Morphological and electrophysiological changes of retina after different light damage in three patients: Three case reports

“…Moreover, the rest of extra photons are absorbed by the retinal pigment epithelium or choroid to avoid heat accumulation[ 11 , 12 ]. However, due to the direct effect of light energy, photoreceptor cells and RPE are also the most vulnerable tissues when the light irradiates abnormally[ 13 ]. Moreover, animal study found müller glia cell activation paticipated in a laser-induced retinal degeneration and regeneration in zebrafish[ 14 ].…”