Abstract
Purpose :
Rod and cone photoreceptors play a central role in visual function. Photoreceptors degenerate in inherited retinal degenerative diseases and age-related macular degeneration. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have shown a link between elevated TH signaling and photoreceptor degeneration. This work investigates the TH regulation of photoreceptor viability using mouse models.
Methods :
Treatment with triiodothyronine (T3) was applied to evaluate the effects of excessive TH signaling. C57BL/6, Thrα1-/- (deletion of TH receptor α1), and Thrβ2-/- (deletion of TH receptor β2) mice at postnatal day 30 received T3 treatment (20 µg/ml in drinking water) for 30 days. Serum T3 level was analyzed by ELISA. Retinal function was evaluated by electroretinogram (ERG). Cone density/number was evaluated by immunolabeling of peanut agglutinin (PNA) on retinal flatmounts and rod number was assessed by measuring the thickness of outer nuclear layer (ONL). Photoreceptor death and oxidative damage were analyzed by TUNEL and immunofluorescence staining of oxidative damage markers 8-OHdG and p-γH2AX. The expression of the cellular stress response genes was evaluated by qRT-PCR.
Results :
Treatment with T3 increased serum T3 level by 2-3 folds compared to the control level. Rod and cone ERG responses were reduced by about 60% and 30%, respectively, after T3 treatment. ONL thickness and cone density were reduced by about 18% and 50%, respectively, after T3 treatment. Retinal sections prepared from T3-treated mice showed significantly increased number of TUNEL-, p-γH2AX-, and 8-OHdG-positive cells. Gene expression analysis showed upregulation of the genes involved in oxidative stress, necroptosis, and inflammatory responses after T3 treatment. Deletion of Thrα1 prevented T3-induced reduction of ONL thickness whereas deletion of Thrβ2 prevented T3-induced reduction of cone density.
Conclusions :
Excessive TH signaling impairs retinal function, induces oxidative stress/damage and apoptosis, and induces rod and cone degeneration. The effects of TH signaling in rods are primarily mediated by Thrα1 whereas the effects of TH signaling in cones are primarily mediated by Thrβ2. This work demonstrates that TH signaling regulates rod and cone photoreceptor viability and TH receptors play differential roles in this regulation.
This is a 2021 ARVO Annual Meeting abstract.