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Nami Nishikiori, Makoto Osanai, Hideki Chiba, Takashi Kojima, Hiroshi Ohguro, Norimasa Sawada; Inhibitory Effects of Retinoic Acid Receptor Alpha Stimulants on Murine Cataractogenesis through Suppression of Deregulated Calpains. Invest. Ophthalmol. Vis. Sci. 2007;48(5):2224-2229. doi: 10.1167/iovs.06-1222.
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purpose. To determine whether retinoic acid (RA)–mediated inhibition of deregulated calpains had any effect on the development of cataract given that accumulating evidence has demonstrated a possible relationship between cataractogenesis and inappropriate activation of calpains.
methods. The authors examined for Ca2+ influx and expression alteration of calpains in F9 cells with or without RAs, such as all-trans retinoic acid (ATRA), and specific stimulant of retinoic acid receptor α (RARα; Am580) in the presence of oxidative stress, such as mediated by H2O2. They next examined the clinical relevance of RAs by applying these agents to a murine diabetic cataract and observed the development of the disease.
results. F9 cells constitute a well-established autonomous cell model for investigating retinoid signaling, partially representing the lens epithelial phenotype, as determined by the expression of aquaporin 0, a specific differentiation marker for lens cells. Treatment with ATRA and Am580 significantly decreased the influx of Ca2+ into the cells, causally resulting in decreased mRNA expression and inhibited activation of calpains. In addition, RARα agonists significantly abrogated the upregulation of calpain 2 induced by H2O2, which is a potential etiological contributor to the diabetic cataract, whereas H2O2 had no effect on calpain 1. Importantly, this RA-mediated gene-expression alteration was sufficient for dramatically inhibiting the development of lens opacity in mice with diabetes.
conclusions. Results showed that a certain type of RA inhibits Ca2+ elevation and subsequent overactivation of calpains, suggesting the potential feasibility of calpain-targeting therapies mediated by RA for cataract.
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