July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Clusterin Enhances Photoreceptor Survival by Suppressing Neuronal Nitric Oxide Synthase (nNOS) Expression Levels in Rhodopsin S334ter-line 3 Retinitis Pigmentosa
Author Affiliations & Notes
  • Cheryl Mae Craft
    USC ROSKI Eye Institute, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
    Integrative Anatomical Sciences, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
  • Andrew J. Vargas
    USC ROSKI Eye Institute, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
  • Kyra Yamamoto
    USC ROSKI Eye Institute, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
  • Justin Li
    USC ROSKI Eye Institute, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
  • LiHui Luo
    USC ROSKI Eye Institute, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
  • Eun Jin Lee
    USC ROSKI Eye Institute, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States
    Biomedical Engineering, USC Viterbi School of Engineering, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Cheryl Craft, None; Andrew Vargas, None; Kyra Yamamoto, None; Justin Li, None; LiHui Luo, None; Eun Jin Lee, None
  • Footnotes
    Support  VSoE Research Innovation Fund (EJL), Research to Prevent Blindness (USC), NH EY015851(CMC), William Hansen Sandberg Memorial Foundation (KY, JL), MDA Foundation (AJ, LL)
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4499. doi:
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      Cheryl Mae Craft, Andrew J. Vargas, Kyra Yamamoto, Justin Li, LiHui Luo, Eun Jin Lee; Clusterin Enhances Photoreceptor Survival by Suppressing Neuronal Nitric Oxide Synthase (nNOS) Expression Levels in Rhodopsin S334ter-line 3 Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4499.

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

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Abstract

Purpose : Retinal environment changes, including oxidative stress, influence photoreceptor degeneration in Retinitis Pigmentosa (RP).1,2 The production of reactive oxygen species causes oxidative damage to proteins, lipids, and DNA.3 Our hypothesis is that clusterin is involved in oxidative stress-induced cell death. We observed a robust preservation of rod photoreceptors in S334ter-line3 retinas with clusterin treatment.4 To explore biochemical pathways influencing oxidative stress, we examined nNOS expression levels before and after treatment of S334ter-line 3 retinas with either clusterin or an inhibitor of nNOS, NG-nitro-L-arginine methyl ester (L-NAME), to determine if rod death is delayed and rod cell survival is prolonged.

Methods : After timed intravitreal injections to RP retinas of clusterin (10µg/ml) or intraperitoneal injection (IP) of L-NAME (100mg/kg), or saline, we studied the effect on their visual responses and nNOS expression levels. Physiological responses were measured using electroretinography (ERG) after treatment, followed by statistical analysis of immunohistochemistry and immunoblots with specific antibodies for nNOS and rhodopsin to investigate the impact of clusterin/L-NAME on nNOS expression and rod survival.

Results : Levels of nNOS are up-regulated in postnatal (P)15, P30, and P60 RP retinas compared to normal and clusterin treatment suppressed expression. Physiological responses using scotopic ERG reveal b-wave amplitudes from clusterin-treated retinas are significantly greater than from saline-treated RP retinas at P30 (P<0.0001) and P45 (P<0.05). In RP retinas, IP injection of L-NAME produced extended protection to delay rod photoreceptor cell death; however, clusterin treatment was more effective in rod survival (P<0.001).

Conclusions : Clusterin acts as a cytoprotective protein to slow the death of rod photoreceptors in RP retinas. Induction of nNOS expression in RP retinas and its down-regulation by clusterin treatment suggests it protects rod photoreceptors by suppressing the up-regulated nNOS levels. Moreover, nNOS/NO induction contributes to photoreceptor death and clusterin provides an important cellular defense mechanism.
1LaVail MM, et al. Exp Eye Res. 2017.
2Cuenca N, et al. Prog Ret & Eye Res. 2014;43:17-75.
3Shen J, et al. J.Cell. Phy. 2005;203(3):457-64.
4Vargas A, et al. PloS one. 2017;12(8):e0182389.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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