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.

PubMed
Abstract

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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