Age-related cataracts in mice lacking the Nrf2 antioxidant transcription factor

Abstract

Purpose : Nrf2 is a critical transcription factor for regulating antioxidant responses to age-related and environmental stresses. Among Nrf2 target genes are phase II antioxidant enzymes like heme oxygenase, catalase, NAD(P)H:quinone oxidoreductase, thioredoxin reductase, and glutamate-cysteine ligase, which are required for maintenance of lens transparency. Nrf2 has been implicated in human cataractogenesis, where the Keap1 negative regulator undergoes promoter demethylation, leading to decreased Nrf2 expression and activity in human cataracts. Despite these associations, non-diabetic mice lacking Nrf2 have not been reported to develop cataracts. Here we tested whether Nrf2-null mice would develop age-related cataracts in the context of high glycemic or low glycemic diets.

Methods : 39 Nrf2-null male mice from a C57BL/6J genetic background were aged to 3-months on a chow diet and then randomized to either high glycemic diets (HG), containing amylopectin as a sole starch source, or low glycemic diets (LG), containing amylose and amylopectin as starch sources. The mice were aged an additional 15-months on diet and were killed at 18-months of age. Lenses were monitored and photographed via slit lamp microscopy and were removed for further histological analysis. Cataracts were scored using a modified LOCSII system.

Results : Nrf2-null mice fed either LG or HG diets had only mild opacities until 1-year of age, at which time 25/31 mice had developed obvious cataracts, some of which continued to worsen with age. Cortical and subcapsular cataracts were most frequently observed, with a lower incidence and severity of nuclear cataract. Several lenses showed complete opacification. No differences in cataract scoring or cataract type were observed between mice fed LG or HG diets. Analysis of neonatal Nrf2-null mice revealed mild abnormalities in central lens epithelial cells and fiber cell organization.

Conclusions : Nrf2-null mice develop multiple opacities with aging, demonstrating essential roles for Nrf2 in the lens. Some of these roles may manifest during development, whereas others require significant accumulation of age-related changes to the lens. Dietary carbohydrate did not significantly alter the incidence or severity of cataracts. Nrf2-null mice thus represent a novel model for senile cataracts and may be promising for testing new therapeutics for the treatment of cataracts.

This is a 2020 ARVO Annual Meeting abstract.