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Xi-Qin Ding, Fan Yang, Michael Robert Butler, Goldis Malek, Hongwei Ma; Thyroid Hormone Regulation of Retinal Pigment Epithelium Morphology and Survival. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1939.
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The retinal pigment epithelium (RPE) plays a critical role in visual function. RPE oxidative damage/dystrophy is at the core of age-related macular degeneration (AMD). Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Clinical observation has shown a link between higher free serum TH values and increased risk of AMD, suggesting that TH signaling may be involved in the pathogenesis of AMD. This work investigates the TH regulation of RPE morphology and survival using mouse models and human RPE cells.
The effects of TH stimulation were evaluated by treatment with triiodothyronine (T3) and deletion of TH receptor. Postnatal day 30 (P30) wild-type (C57BL/6), Thrα1-/-, and Thrβ2-/- mice received T3 (4 µg/g/day, s.c. or in drinking water) for 30 days, and were then analyzed for RPE morphology by immunolabeling of the tight junction protein-1 (ZO-1) on RPE flatmounts. Image analysis was performed using ImageJ and CellProfiler software. The effects of TH signaling suppression were evaluated in a sodium iodate (NaIO3)-induced model of RPE stress/damage. Wild-type, Thrα1-/-, Thrβ-/-, and Thrβ2-/- mice received a bolus injection of NaIO3 (30 mg/kg, i.p.) or vehicle at P30. Three days after treatment with NaIO3, mice were evaluated for RPE morphology and cell death. In addition, the effects of TH receptor inhibition were evaluated in the human ARPE-19 cells and human primary RPE cells after challenged with NaIO3, using a TH receptor antagonist.
Treatment with T3 increased serum T3 level by 2-3 folds relative to the control level. This treatment significantly impaired mouse RPE morphology. Morphometric measurements showed disruption of regular cell size and shape of RPE in C57BL/6 mice that have been treated with T3. Deletion of Thrα1-/- or Thrβ2-/- reversed effects of T3 treatment. The RPE in C57BL/6 mice treated with NaIO3 showed severe cell loss and enhanced expression of the oxidative stress genes. Deletion of TH receptor significantly improved RPE morphology and reduced cell loss. Treatment with TH receptor antagonist MLS000389544 protected ARPE-19 cells from NaIO3-induced death.
This work shows that TH signaling stimulation harms RPE whereas TH signaling suppression protects RPE against oxidative stress/damage. Our findings suggest that TH signaling may play a role in the pathogenesis of AMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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