June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Impaired Chromophore Availability in the Diabetic Retina: Impact on Visual Performance
Author Affiliations & Notes
  • Bruce Berkowitz
    Anatomy/Cell Biol & Ophthal, Wayne State Univ Sch of Med, Detroit, MI
  • Timothy Kern
    Pharmacology, Case Western Reserve University, Cleveland, OH
    Stokes VA Medical Center, Cleveland, OH
  • Vladimir Kefalov
    Ophthalmology, Washington University in St. Louis, St. Louis, MO
  • Johannes Von Lintig
    Pharmacology, Case Western Reserve University, Cleveland, OH
  • Robin Roberts
    Anatomy/Cell Biol & Ophthal, Wayne State Univ Sch of Med, Detroit, MI
  • David Bissig
    Anatomy/Cell Biol & Ophthal, Wayne State Univ Sch of Med, Detroit, MI
  • Footnotes
    Commercial Relationships Bruce Berkowitz, None; Timothy Kern, Bausch & Lomb (F), PamLab (F); Vladimir Kefalov, None; Johannes Von Lintig, None; Robin Roberts, None; David Bissig, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 2680. doi:https://doi.org/
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      Bruce Berkowitz, Timothy Kern, Vladimir Kefalov, Johannes Von Lintig, Robin Roberts, David Bissig; Impaired Chromophore Availability in the Diabetic Retina: Impact on Visual Performance. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2680. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To test the hypothesis that subnormal intraretinal ion channel activity and visual performance measured in diabetic mice are due to inadequate availability of chromophore.

Methods: Diabetic and non-diabetic age-matched C57Bl/6 mice and rd12 mice (RPE65 mutant) were dark adapted for either 1 day (1dDA) or 5 days (5dDA). 5dDA groups: controls (without or with matrigel s.q.) or treated (matrigel and 9-cis-retinal (PMID: 20574023) mice. Intraretinal L-type voltage gated calcium channel (VGCC) activity in vivo was evaluated using manganese-enhanced MRI (MEMRI). Spatial frequency threshold (SFT) and contrast sensitivity (CS) were measured with optokinetic tracking. Parallel ex vivo transretinal electrophysiological studies were also performed from 1dDA mice. A subset of the diabetic retinas was treated with 100 µM 11-cis retinal prior to recordings. Steady-state levels of 11-cis-retinal, all-trans-retinal, and retinyl esters were also measured.

Results: In 5dDA controls, retinal VGCCs on MEMRI are not sustained in the open position (i.e., they are closed or “dark desensitized”) but were opened upon treatment with the chromophore surrogate 9-cis-retinal. However, visual performance did not decrease following extended darkness and was not altered by 9-cis-retinal treatment. In contrast, overnight dark adapted diabetic mice (before the appearance of microangiopathy) had inappropriately closed photoreceptor L-VGCCs on MEMRI which partly opened with five days of darkness. The ion channels in photoreceptors from diabetic mice were regulated by darkness in a manner similar to that in normoglycemic rd12 mice (an “equivalent light” model). Ex vivo transretinal ERG sensitivity was reduced about 2-fold in diabetic mice (and accordingly, I1/2 is increased about 2-fold). The effects were largely reversed by the application of 11-cis retinal. Changes in retinoid metabolism (particularly chromophore production) were found consistent with increased production of free opsin. In vivo, 5dDA diabetic mice treated with 9-cis-retinal had significantly opened outer retinal channels (MEMRI) and corrected diabetic visual impairment.

Conclusions: Diabetes-evoked reduction in photoreceptor chromophore availability contributes to the associated visual performance dysfunction.

Keywords: 499 diabetic retinopathy • 648 photoreceptors • 705 retinoids/retinoid binding proteins  
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