Aged Nrf2-Null Mice Develop All Major Types of Age-Related Cataracts

Abstract

Purpose Age-related cataracts affect the majority of older adults and are a leading cause of blindness worldwide. Treatments that delay cataract onset or severity have the potential to delay cataract surgery, but require relevant animal models that recapitulate the major types of cataracts for their development. Unfortunately, few such models are available. Here, we report the lens phenotypes of aged mice lacking the critical antioxidant transcription factor Nfe2l2 (designated as Nrf2 −/−). Methods Three independent cohorts of Nrf2 −/− and wild-type C57BL/6J mice were evaluated for cataracts using combinations of slit lamp imaging, photography of freshly dissected lenses, and histology. Mice were fed high glycemic diets, low glycemic diets, regular chow ad libitum, or regular chow with 30% caloric restriction. Results Nrf2 −/− mice developed significant opacities between 11 and 15 months and developed advanced cortical, posterior subcapsular, anterior subcapsular, and nuclear cataracts. Cataracts occurred similarly in male mice fed high or low glycemic diets, and were also observed in 21-month male and female Nrf2 −/− mice fed ad libitum or 30% caloric restriction. Histological observation of 18-month cataractous lenses revealed significant disruption to fiber cell architecture and the retention of nuclei throughout the cortical region of the lens. However, fiber cell denucleation and initiation of lens differentiation was normal at birth, with the first abnormalities observed at 3 months. Conclusions Nrf2 −/− mice offer a tool to understand how defective antioxidant signaling causes multiple forms of cataract and may be useful for screening drugs to prevent or delay cataractogenesis in susceptible adults.

Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects

“…Interestingly, Pxdn has recently been recognized to be a target of the TF Nrf2 (Hanmer and Mavri-Damelin, 2018), which is an established partner protein of small Mafs, binding together of which impact their downstream control over target genes (Katsuoka et al, 2005). Further, Nrf2 deficiency is associated with lens defects and cataract (Rowan et al, 2021). Thus, overexpression of Pxdn, resulting from Mafg, Mafk deletion, may impact cell proliferation and altered ECM, which together contribute to the epithelial defects observed in Mafg −/− :Mafk −/− lens.…”

Loss of fiber cell communication may contribute to the development of cataracts of many different etiologies

“…Recently, it was shown that mice with homozygous deletion of the gene encoding nuclear factor erythroid 2–related factor 2 (Nrf2, also known as Nfe2l2) develop significant cataracts late in life (11–15 months of age) at a higher frequency than wild-type mice of comparable ages ( Rowan et al, 2021 ). Although the mechanism responsible for development of these cataracts has not been determined, it is possible that these mice have less protection against oxidative stress and therefore age faster.…”

Potential Properties of Natural Nutraceuticals and Antioxidants in Age-Related Eye Disorders

“…In physiological conditions, Keap1 can increase the nuclear factor and erythroid 2-related factor 2 (Nrf2) proteasomal degradation. Since Nrf2 controls the basal and induced expression of a number of antioxidant-response genes, it is evident that the reduction of Keap1-induced ROS increases the degradation of Nrf2 and, as a result, reduces a cell’s antioxidant control system [ 53 , 54 , 55 ]. The consequence is that oxidative damage increases exponentially, along with the development of cataracts of the lens.…”