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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Cell Death / drug effects
  • Cell Death / radiation effects
  • Cells, Cultured
  • Diet*
  • Disease Models, Animal
  • Light / adverse effects*
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NAD / metabolism
  • Photoreceptor Cells, Vertebrate / drug effects*
  • Photoreceptor Cells, Vertebrate / metabolism
  • Photoreceptor Cells, Vertebrate / pathology
  • Photoreceptor Cells, Vertebrate / radiation effects*
  • Rats
  • Rats, Sprague-Dawley
  • Retinal Degeneration / etiology
  • Retinal Degeneration / genetics
  • Retinal Degeneration / metabolism
  • Retinal Degeneration / pathology
  • Retinal Degeneration / prevention & control*
  • Rhodopsin / metabolism
  • Time Factors
  • Tomography, Optical Coherence
  • Zinc / administration & dosage
  • Zinc / metabolism
  • Zinc / toxicity*
  • cis-trans-Isomerases / deficiency
  • cis-trans-Isomerases / genetics


  • Carrier Proteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Slc30a3 protein, mouse
  • NAD
  • Rhodopsin
  • retinoid isomerohydrolase
  • cis-trans-Isomerases
  • Zinc