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D. Simic, S. Deng, C. J. Somps; Drug-Induced Lens Toxicity and Differential Expression of miRNA. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2780. doi: https://doi.org/.
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In mammals, microRNAs (miRNAs) regulate translation through repressive binding to the 3’-UTR of the target mRNA. miRNAs control a wide range of cellular functions and have been shown to play key roles in development, inflammation, cancer, and diabetes. The purpose of this study was to determine if miRNA expression is altered in isolated ocular lens tissues treated with known lenticular toxicants.
To assess drug-induced miRNA expression in lens, we treated rat lens explants and primary rat lens epithelial cells (rLECs) with compounds previously shown to induce lens toxicity in vivo and/or ex vivo. Lens explants and rLECs were treated for 48h with cataractogens, Ciglitazone (15µM), ZD2138 (100µM) or control media. rLECS were also treated with a ‘negative control’ (25µM), a Pfizer compound that didn’t cause any ocular toxicity in rat or dog studies. Cells and tissues were processed using mirVana miRNA Isolation Kit (Ambion). Cells were analyzed using miRNA probe loaded TaqMan Low Density Array (TLDA) plates (ABI) and lens tissues were analyzed using the Ambion mirVana Bioarray 1566V2 (Asuragen). The data was visualized using principal component analysis (PCA) and multi-dimensional scaling (MDS) plots. Differential expression of miRNAs was quantified by comparison to expression in control groups through ANOVA model and fold-change analysis.
PCA and MDS plots of miRNA expression show that positive cataractogenic compounds cluster together and away from the control and/or the negative compound. By using two different platforms (Bioarray chip and RT-PCR) we have identified three differentially expressed miRNAs (miR-31 and miR-99a/b) in lens tissues treated with lens toxicants in both platforms. Using target predictive tools miR-99a and 99b seem to regulate actin cytoskeleton and integrin signaling pathway while miR-31 is involved in regulation of cell cycle and proliferation both of which are important in correct lens function and integrity.
These results indicate that miRNA expression in the lens is altered by drugs that cause lens toxicity and that their differential expression may be used to understand toxicity pathways and/or as biomarkers of lens toxicity.
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