Aminoguanidine-treatment results in the inhibition of lens opacification and calpain-mediated proteolysis in Shumiya cataract rats (SCR)

The Shumiya cataract rat (SCR) is a hereditary cataract model in which lens opacity appears spontaneously in the nuclear and perinuclear portions at 1 1-12 weeks of age. We found incidentally that the oral administration of am inoguanidine (AG), an inhibitor of inducible nitric oxide synthase (iNOS), strongly inhibits the development of lens opacification in SCR, Since our p revious results strongly suggested that calpain-mediated proteolysis contri butes to lens opacification during cataract formation. in SCR, we examined the calpain-mediated proteolysis in AG-treated SCR lenses in detail. The re sults show that the calpain-mediated limited proteolysis of crystallins is also inhibited by AG-treatment, However, the administration of AG has no ef fect on the substrate susceptibility to calpain, On the other hand, the aut olytic activation of calpain in AG-treated lenses is strongly inhibited, al though AG itself does not inhibit calpain activity in vitro. Then, we analy zed the effect of AG-treatment on calcium concentrations in lens, and found that the elevation in calcium concentration that should occur prior to cat aractogenesis in lenses is strongly suppressed by AG-treatment, These resul ts strengthen our previous conclusion that calpain-mediated proteolysis pla ys a critical role in the development of lens opacification in SCR, Moreove r, our results indicate that the inhibition of calpain-mediated proteolysis by AG-treatment is due to the suppression of calcium ion influx into the l ens cells.