GPX1 knockout, not catalase knockout, causes accelerated abnormal optical aberrations and cataract in the aging lens

Glutathione peroxidase 1 (GPX1) and catalase are expressed in the lens epithelial cells and cortical fiber cells, where they detoxify H2O2 to reduce oxidative stress, which is a major cause for cataractogenesis. We sought to find out, between these two enzymes, which is critical for transparency and homeostasis in the aging lens by investigating alterations in the lens's refractive property, transparency, and gap junction coupling (GJC) resistance.

Wild-type (C57BL/6J), GPX1 knockout (GPX1^-/-) and catalase knockout (CAT^-/-) mice were used. Lens transparency was quantified using dark-field images and ImageJ software. For optical aberration evaluation, each lens was placed over a copper electron microscopy specimen grid; the grid image was captured through the lens using a digital camera attached to a dark-field binocular microscope. Optical aberrations were assessed by the quality of the magnified gridlines. Microelectrode-based intact lens intracellular impedance was measured to determine GJC resistance.

In contrast to wild-type (WT) and CAT^-/- lenses, GPX1^-/- lenses developed accelerated age-related cataracts. While two-month-old lenses were normal, at nine months of age, GPX1^-/- mice started to show the development of abnormal optical distortion aberrations and loss of transparency. At 12 months of age, GPX1^-/- lenses developed significant opacity and abnormal optical distortion aberrations compared to CAT^-/- and WT (p<0.001); these aberrations gradually increased with age and matured into cataracts by 24 months of age. There was also a significant increase (p<0.001) in GJC resistance in the differentiating and mature fiber cells of GPX1^-/- lenses at 12 months of age compared to that in similar areas of age-matched CAT^-/- and WT lenses.

Changes in the refractive and physiological properties of the lens occurred before cataract formation in GPX1^-/- lenses but not in CAT^-/- lenses. GPX1 is more critical than catalase for lens transparency, optical quality, and homeostasis in the aging lens under normal physiological conditions. GPX1 could be a promising therapeutic target for developing potential strategies to reduce adverse oxidative stress and delay/treat/prevent age-related cataracts.