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(Investigative Ophthalmology and Visual Science. 2007;48:2224-2229.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-1222
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Inhibitory Effects of Retinoic Acid Receptor Alpha Stimulants on Murine Cataractogenesis through Suppression of Deregulated Calpains

Nami Nishikiori,1,2 Makoto Osanai,1 Hideki Chiba,1 Takashi Kojima,1 Hiroshi Ohguro,2 and Norimasa Sawada1

1From the Departments of Pathology and 2Ophthalmology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Japan.

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 {alpha} (RAR{alpha}; 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, RAR{alpha} 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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Copyright © 2007 by the Association for Research in Vision and Ophthalmology