Abstract
The Shumiya cataract rat (SCR) is a model for hereditary cataract. Two-thirds of these rats develop lens opacity within 10-11 weeks. Onset of cataract is attributed to the synergetic effect of lanosterol synthase (Lss) and farnesyl-diphosphate farnesyltransferase 1 (Fdft1) mutant alleles that lead to cholesterol deficiency in the lenses, which in turn adversely affects lens biology including the growth and differentiation of lens epithelial cells (LECs). Nevertheless, the molecular events and changes in gene expression associated with the onset of lens opacity in SCR are poorly understood. In the present study, a microarray-based approach was employed to analyze comparative gene expression changes in LECs isolated from the precataractous and cataractous stages of lenses of 5-week-old SCRs. The changes in gene expression observed in microarray results in the LECs were further validated using real-time reverse transcribed quantitative PCR (RT-qPCR) in 5-, 8-, and 10-week-old SCRs. A mild posterior and cortical opacity was observed in 5-week-old rats. Expressions of approximately 100 genes, including the major intrinsic protein of the lens fiber (Mip and Aquaporin 0), deoxyribonuclease II beta (Dnase2B), heat shock protein B1 (HspB1), and crystallin γ (γCry) B, C, and F, were found to be significantly downregulated (0.07-0.5-fold) in rat LECs derived from cataract lenses compared to that in noncataractous lenses (control). Thus, our study was aimed at identifying the gene expression patterns during cataract formation in SCRs, which may be responsible for cataractogenesis in SCR. We proposed that cataracts in SCR are associated with reduced expression of these lens genes that have been reported to be related with lens fiber differentiation. Our findings may have wider implications in understanding the effect of cholesterol deficiency and the role of cholesterol-lowering therapeutics on cataractogenesis.
Highlights
Age-related eye disease is a serious public health issue, and age-related cataract is the leading cause of blindness worldwide [1]
In CatSCR, the lens was clear, at 5 and 10 weeks of age, but in the case of Cat + Shumiya cataract rat (SCR), a mild posterior and cortical opacity was observed at 5 weeks of age, and severe cortical and nuclear opacity was observed at age 10 weeks (Figure 1)
The data for the microarray analysis was deposited to the Gene Expression Omnibus (GEO) database (Accession number: GSE152616)
Summary
Age-related eye disease is a serious public health issue, and age-related cataract is the leading cause of blindness worldwide [1]. Lenses have almost no protein turnover and are susceptible to ultraviolet rays, oxidative stress, and glycative stress. Recent studies have shown that oxidative stress controls various cellular processes associated with cell survival, such as cell proliferation, differentiation, aging, and cell death. It promotes cell apoptosis and senescence and is associated with many diseases [5, 6]. Oxidative stress and reactive oxygen species (ROS) are a major cause of age-related eye diseases, and diets rich in BioMed Research International fruits, vegetables, vitamin C, zeaxanthin, lutein, and multivitamin-mineral supplements are recommended for preventing cataracts and age-related macular degeneration [7,8,9,10]. Several risk factors such as advancing age, genetic predisposition, oxidative stress, and external and internal factors acting adversely on lens homeostasis have been implicated to contribute to the etiology of cataract formation
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