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Fan Yang, Hongwei Ma, Josh Belcher, Michael Redmond, Xi-Qin Ding; Inhibition of Type II Iodothyronine Deiodinase Preserves Cones in Mouse Models of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):181.
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© ARVO (1962-2015); The Authors (2016-present)
Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. In the retina, TH signaling plays a central role in cone opsin expression. Suppressing thyroid hormone (TH) signaling by anti-thyroid treatment reduces cone death in retinal degeneration mice. The intracellular TH signaling is regulated by the type II iodothyronine deiodinase (DIO2) which catalyzes the conversion of the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3). This work investigates the effectiveness of inhibition of DIO2 in cone protection.
Inhibition of DIO2 was achieved by the use of the pharmacological inhibitor iopanoic acid (IOP). The effects of IOP were first tested in the photoreceptor-derived WERI-Rb1 cells. We pretreated cells with IOP for 16 hours, followed by treatment with T4 for 24 hours. At the end of the experiments, cells were harvested for analysis of mRNA expression of M-opsin by q-RT PCR. In the animal drug treatment experiments, postnatal day 7 (P7) Rpe65-/- or Rpe65-/-/Nrl-/- mice were intravitreally injected with IOP or vehicle. Mice were analyzed for cone death by terminal deoxynucleotidyltransferase dUTP nick end-labeling (TUNEL) at P15, and for cone density by immunofluorescence labeling of cone markers at P25. Expression of DIO2 in the mouse retina was examined by immunofluorescence labeling.
We found that IOP inhibited T4-induced M-opsin expression in WERI cells in a concentration-dependent pattern, and treatment with IOP significantly improved cone survival in retinal degeneration mice. The number of TUNEL-positive cells in IOP-treated Rpe65-/-/Nrl-/- mice decreased by about 25%, compared with vehicle-treated controls. Cone density, evaluated by labeling of peanut agglutinin (PNA), cone arrestin (CAR), and cone opsin, increased significantly in IOP-treated Rpe65-/- mice, compared with vehicle-treated controls. The expression study showed that DIO2 immunoreactivity was detected in the inner segment area, and it co-localized with ATPase α1, which is consistent with its primary localization to the endoplasmic reticulum.
Our results show that pharmacological inhibition of DIO2 in the retina reduces cone death in retinal degeneration mice. The findings of this work provide insights into cone preservation and therapeutic interventions in retinal degeneration.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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