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Targeting Retinoic Acid Receptor-Related Orphan Receptor α to Prevent Cataracts: A New Pathway Through Nerve Growth
Zhenyu Wang1, Jinda Wang1, Xuemin Li2
1Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Capital Medical University, Beijing, China.
Aims:
Cataracts are the leading cause of blindness worldwide, and the mechanism underlying cataract formation is linked to the oxidative damage and the apoptosis of lens epithelial cells. Retinoic acid Receptor-related orphan receptor α (RORα), a transcription factor, prevents oxidative stress and cell apoptosis. RORα is decreased in the lens from patients with cataract, but it remains unclear whether decreases in RORα are attributed to cataract formation.
Results:
Here, rat models of selenite-induced cataracts were used for in vivo experiments. In vitro, human lens epithelial cells (SRA01-04) were treated with selenite. RORα was downregulated in the lens from rat models of selenite-induced cataracts. The RORα agonist SR1078 significantly mitigated the degree of lens opacity. SR1078 reduced oxidative stress, cell apoptosis, and mitochondrial dysfunction and promoted the peroxisome proliferative activated receptor gamma coactivator (PGC-1α) and the nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 pathways in the lens from rat models of selenite-induced cataracts and lens epithelial cells upon selenite stimulation. RORα overexpression showed a similar protective effect on lens epithelial cells in vitro. Nerve growth factor (NGF) expression was up-regulated by RORα overexpression. Although RORα overexpression prevented selenite-induced damage to lens epithelial cells, the damage recurred following NGF knockdown.
Conclusion:
RORα protects against selenite-induced oxidative stress and cellular apoptosis. In the context of cataractogenesis, NGF is newly identified as a transcriptional target of RORα, and its reduction is related to mitochondrial dysfunction in lens epithelial cells. Our study highlights the translational potential of RORα activation as a nonsurgical cataract intervention. Antioxid. Redox Signal. 44, 599-617.
Insights
Retinoic acid Receptor-related orphan receptor α (RORα) activation protects against oxidative stress and apoptosis, offering a potential nonsurgical treatment for cataracts. This study identifies nerve growth factor (NGF) as a key target of RORα in preventing lens cell damage.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cataracts are a leading cause of global blindness, primarily driven by oxidative damage and lens epithelial cell apoptosis.
- Retinoic acid Receptor-related orphan receptor α (RORα), a crucial transcription factor, is known to protect against oxidative stress and apoptosis.
- Reduced RORα levels are observed in cataractous lenses, but its direct role in cataractogenesis remains unclear.
Purpose of the Study:
- To investigate the protective role of RORα against selenite-induced cataract formation.
- To elucidate the molecular mechanisms by which RORα exerts its protective effects in lens epithelial cells.
- To identify potential therapeutic targets for nonsurgical cataract intervention.
Main Methods:
- Establishment of rat models for selenite-induced cataracts and in vitro studies using human lens epithelial cells (SRA01-04) treated with selenite.
- Administration of RORα agonist SR1078 and RORα overexpression to assess protective effects.
- Analysis of oxidative stress markers, apoptosis, mitochondrial function, and key signaling pathways (PGC-1α, Nrf2-HO-1, NGF).
Main Results:
- Selenite-induced cataracts showed downregulation of RORα in rat lenses.
- SR1078 treatment significantly reduced lens opacity, oxidative stress, apoptosis, and mitochondrial dysfunction, while promoting PGC-1α and Nrf2-HO-1 pathways.
- RORα overexpression protected lens epithelial cells, upregulating NGF expression; however, NGF knockdown led to recurrent damage, indicating its critical role downstream of RORα.
Conclusions:
- RORα activation demonstrates significant protective effects against selenite-induced oxidative stress and apoptosis in lens epithelial cells.
- Nerve growth factor (NGF) is identified as a novel transcriptional target of RORα, crucial for preventing mitochondrial dysfunction and cataractogenesis.
- RORα activation holds translational potential as a promising nonsurgical therapeutic strategy for cataract intervention.
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