Potential Elevation of Thyroid Hormone Signaling in Mouse Retinal Pigment Epithelium and Retina after Oxidative Stress Challenge

Abstract

Purpose : Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have shown that suppressing TH signaling protects photoreceptors and retinal pigment epithelium (RPE) in an oxidative stress-related mouse model of age-related macular degeneration. This work investigates TH signaling activity in mouse retina and RPE after oxidative stress challenge to understand how suppression of TH signaling leads to retinal protection.

Methods : C57BL/6J and Nrl^-/- mice received a single injection of NaIO₃ (30 mg/kg, i.p.) or vehicle on postnatal day 30. At day 1 and 3 post-NaIO₃ injection, RPE and retinas were collected and evaluated for expression of genes involved in TH signaling. These include genes encoding TH receptors, enzymes involved in metabolism of TH, and TH transporters, using qRT-PCR. In a separate experiment, hRPE cells were treated with NaIO₃ at various concentrations (0, 20, 40 mM) for 24 hours, and then evaluated for gene expression.

Results : Expression of Thrb2 (encoding B2 type of TH receptor), Dio2 (encoding type 2 iodothyronine deiodinase), and Mct10 (encoding monocarboxylate transporter 10) in the mouse RPE was increased by about 6-10-fold after NaIO₃ treatment. Similarly, hRPE cells showed significant upregulation of Mct10, Itgav (encoding TH membrane receptor integrin subunit alpha V), and Dio3 (encoding type 3 iodothyronine deiodinase) after NaIO₃ treatment. Expression of Thra1 (encoding A1 type of TH receptor), Itgav, Itgb3 (encoding TH membrane receptor integrin subunit beta 3), and Dio3 in the retinas of C57BL/6J mice (rod-dominant) were significantly increased after NaIO₃ treatment. Expression of Itgb3, MCT8 (encoding monocarboxylate transporter 8), Mct10, and Dio3 in the retinas of Nrl^-/- mice (cone-dominant) were significantly increased after NaIO₃ treatment.

Conclusions : Oxidative stress challenge induces expression of genes involved in TH signaling in mouse RPE and retina, suggesting increased TH signaling activity. The gene expression alterations in the retina are distinct from that in the RPE, and the alterations in the rod-dominant retina are somewhat different from that in the cone-dominant retina, suggesting a local/microenvironmental regulation of TH signaling in response to oxidative stress challenge.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.