July 2018
Volume 59, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2018
Suppressing thyroid hormone signaling reduces cellular necroptosis and oxidative stress in retinas of LCA model Rpe65-deficient mice
Author Affiliations & Notes
  • Xi-Qin Ding
    Cell Biology, Univ Oklahoma Hlth Sciences Ctr, Oklahoma City, Oklahoma, United States
  • Fan Yang
    Cell Biology, Univ Oklahoma Hlth Sciences Ctr, Oklahoma City, Oklahoma, United States
  • Hongwei Ma
    Cell Biology, Univ Oklahoma Hlth Sciences Ctr, Oklahoma City, Oklahoma, United States
  • Footnotes
    Commercial Relationships   Xi-Qin Ding, None; Fan Yang, None; Hongwei Ma, None
  • Footnotes
    Support  This work was supported by grants from the National Eye Institute (P30EY021725 and R21EY024583), the Foundation Fighting Blindness, and the Knights Templar Eye Foundation.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4965. doi:
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    • Get Citation

      Xi-Qin Ding, Fan Yang, Hongwei Ma; Suppressing thyroid hormone signaling reduces cellular necroptosis and oxidative stress in retinas of LCA model Rpe65-deficient mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4965.

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

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Abstract

Purpose : Suppressing thyroid hormone (TH) signaling protects cones in retinal degeneration model mice, including the Leber congenital amaurosis (LCA) Rpe65-deficient mice. Using anti-thyroid treatment and deletion of the type 2 iodothyronine deiodinase (Dio2), the enzyme converting the prohormone thyroxine to the active hormone triiodothyronine (T3), we examined effects of TH signaling suppression on the cellular stress/death pathways in Rpe65-deficient mice to understand how TH signaling suppression protects cones.

Methods : Due to the sparse amount of cones in mammalian retinas the cone-dominant Nrl-/--background mice were used. Rpe65-/- and Rpe65-/-/Nrl-/- mice were used to examine the effects of anti-thyroid treatment using methimazole and sodium perchlorate monohydrate; Rpe65-/-/Dio2-/+, Rpe65-/-/Dio2-/-, Rpe65-/-/Nrl-/-/Dio2-/+, and Rpe65-/-/Nrl-/-/Dio2-/- mice were used to examine the effects of Dio2 deletion; and Nrl-/- mice were used to examine the effects of TH signaling stimulation with T3 treatment. Mice were analyzed for retinal function by electroretinography, cone density and cell death by immunofluorescence detection, and expression levels of necroptosis and oxidative stress genes by qRT-PCR and immunoblotting.

Results : Rpe65-deficient mice showed increased expression of necroptosis genes, including Ripk3, Tnfα, Tnfr1 and Tradd, and oxidative stress genes, including Gpx4, Ucp2, Gss, Ctsb, Ncf1, and Ehd2. Treatment with anti-thyroid drug significantly reduced alterations of these genes. Deletion of Dio2 improved cone function and survival in Rpe65-/- and Rpe65-/-/Nrl-/- mice, accompanied by reduced necroptosis and oxidative stress responses. Moreover, treatment with T3 induced cone death in Nrl-/- mice, accompanied by increased expression of the necroptosis and oxidative stress genes.

Conclusions : The LCA model Rpe65-deficient mice show increased cellular necroptosis and oxidative stress, and suppressing TH signaling by anti-thyroid treatment or deletion of Dio2 significantly inhibits these cellular events. Furthermore, treatment with T3 promotes necroptosis and oxidative stress in the mouse retina. Findings from this work suggest TH signaling suppression-induced inhibition of cellular necroptosis and oxidative stress might attribute to the observed cone protection.

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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