The study of the mechanism of cataract formation using aminoguanidine, which has the ability to prevent lens opacification.

Shumiya白内障大鼠（SCR）是一种遗传性白内障模型，在11-12周龄时，晶状体在核和核周部分自发出现混浊。我们偶然发现，口服氨基胍（AG）强烈抑制SCR晶状体混浊的发展。由于我们之前的研究结果表明calpain介导的蛋白水解有助于白内障形成过程中的晶状体混浊，因此我们在ag处理的SCR晶状体中检测了calpain介导的蛋白水解。结果表明，ag处理可抑制calpain介导的晶体蛋白有限蛋白水解。然而，AG的施用对底物对钙蛋白酶的敏感性没有影响。另一方面，AG处理的晶状体中calpain的自溶激活被抑制，尽管AG本身在体外并不抑制calpain的活性。然后，我们分析了ag处理对晶状体中钙浓度的影响，发现在白内障发生之前晶状体中钙浓度的升高被ag处理强烈抑制。AG是诱导型一氧化氮合酶（inducible nitric oxide synthase, iNOS）的抑制剂，因此确认iNOS是否在白内障晶状体中高表达具有重要意义。因此，我们研究了iNOS是否上调并参与白内障的形成。与正常晶状体相比，白内障晶状体中iNOS mRNA和iNOS蛋白表达水平较高。口服AG可明显抑制其表达的增加，从而防止晶状体混浊。在钙含量升高和钙蛋白酶介导的蛋白水解加速之前，观察到iNOS蛋白的诱导，这两者与晶状体混浊的发生密切相关。这些发现强烈提示iNOS参与了SCR白内障的形成。可以想象，iNOS的上调导致钙流入晶状体细胞并随后激活钙蛋白酶。少

The Shumiya cataract rat (SCR) is a hereditary cataract model in which lens opacity appears spontaneously in the nuclear and perinuclear portions at 11-12 weeks of age. We found incidentally that the oral administration of aminoguanidine (AG) strongly inhibits the development of lens opacification in SCR. Since our previous results suggested that calpain-mediated proteolysis contributes to lens opacification during cataract formation, we examined the calpain-mediated proteolysis in AG-treated SCR lenses. The results showed that the calpain-mediated limited proteolysis of crystallins is inhibited by AG-treatment. However, the administration of AG had no effect on the substrate susceptibility to calpain. On the other hand, the autolytic activation of calpain in AG-treated lenses was inhibited, although AG itself did not inhibit calpain activity in vitro. Then, we analyzed the effect of AG-treatment on calcium concentrations in lens, and found that the elevation in calcium concentration t … More hat should occur prior to cataractogenesis in lenses is strongly suppressed by AG-treatment. Since AG is an inhibitor of inducible nitric oxide synthase (iNOS), it is of interest and significance to confirm whether iNOS is highly expressed in cataractous lenses. Therefore, we examined whether iNOS is upregulated and involved in cataract formation. High levels of iNOS mRNA and iNOS protein were expressed in cataractous lenses compared with normal lenses. The increase in their expressions was markedly suppressed by the oral administration of AG, which acts to prevent lens opacification. The induction of iNOS protein was observed before the elevation of calcium content and the acceleration of calpain-mediated proteolysis, both of which are closely related to the development of lens opacification. These findings strongly suggest that iNOS is involved in cataract formation in SCR. It is conceivable that upregulation of iNOS causes the calcium influx into lens cells and subsequent activation of calpain. Less