Inhibitory effects of retinoic acid receptor alpha stimulants on murine cataractogenesis through suppression of deregulated calpains.
OBJECTIVE
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 Ca(2+) 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 (RARalpha; Am580) in the presence of oxidative stress, such as mediated by H(2)O(2). 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 Ca(2+) into the cells, causally resulting in decreased mRNA expression and inhibited activation of calpains. In addition, RARalpha agonists significantly abrogated the upregulation of calpain 2 induced by H(2)O(2), which is a potential etiological contributor to the diabetic cataract, whereas H(2)O(2) 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 Ca(2+) elevation and subsequent overactivation of calpains, suggesting the potential feasibility of calpain-targeting therapies mediated by RA for cataract.
Nishikiori
Nami
N
Departments of Pathology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Japan. nami731978@sapmed.ac.jp
Osanai
Makoto
M
Chiba
Hideki
H
Kojima
Takashi
T
Ohguro
Hiroshi
H
Sawada
Norimasa
N
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D002386:Cataract / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D006861:Hydrogen Peroxide / Q000633:toxicity; D007908:Lens, Crystalline / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D001565:Benzoates; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; C068073:Am 580; D014212:Tretinoin; D006861:Hydrogen Peroxide; D002154:Calpain; D002118:Calcium