Redox Regulation in Age-Related Cataracts: Roles for Glutathione, Vitamin C, and the NRF2 Signaling Pathway

Abstract

Age is the biggest risk factor for cataracts, and aberrant oxidative modifications are correlated with age-related cataracts, suggesting that proper redox regulation is important for lens clarity. The lens has very high levels of antioxidants, including ascorbate and glutathione that aid in keeping the lens clear, at least in young animals and humans. We summarize current functional and genetic data supporting the hypothesis that impaired regulation of oxidative stress leads to redox dysregulation and cataract. We will focus on the essential endogenous antioxidant glutathione and the exogenous antioxidant vitamin C/ascorbate. Additionally, gene expression in response to oxidative stress is regulated in part by the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2 [NFE2L2]), thus we will summarize our data regarding cataracts in Nrf2-/- mice. In this work, we discuss the function and integration of these capacities with the objective of maintaining lens clarity.

Keywords: NRF2; ascorbate/vitamin C; glutathione; lens; redox.

Figure 1

Eye and lens structure and cataract. (A) Cross section of the eye showing light passing through the cornea and lens. (B) Lens section illustrating the epithelial layer, fiber cell differentiation and the organelle-free zone. (C) different cataract types.

Figure 2

Interactions between antioxidant pathways. NRF2 increases the transcription of GCLM and GCLC, rate limiting enzymes in glutathione synthesis. GSH and ascorbate coordinate cellular redox by reducing and oxidizing each other.

Figure 3

Deletion of Nrf2 leads to age-related cataracts. Examples are shown of 18 months wild-type or Nrf2-/- lenses. These cataracts contain nuclear, cortical and capsular opacities, resulting in the blocking of light to the retina.