PURPOSE. Maintaining appropriate osmotic pressure is essential for maintaining lens transparency. This study was performed to investigate whether high levels of myo-inositol, one of the major organic osmolytes in the lens, would lead to cataract development. METHODS. Transgenic mouse lines carrying the bovine Na ϩ -dependent myo-inositol transporter (bSMIT) cDNA under the control of the mouse ␣A-crystallin promoter were generated. RESULTS. Increased bSMIT expression was accompanied by increased myo-inositol level in the lens and increased uptake of ( 3 H) myo-inositol by the lens in culture. The transgenic mice developed observable cataract under normal rearing conditions beginning at 2 to 8 weeks of age, and the severity of cataract development was correlated to the level of bSMIT gene expression and lens myo-inositol accumulation. For transgenic mouse line 3352, heterozygous mice did not develop cataract, whereas homozygous ones did. Prenatal feeding of heterozygous 3352 mice with high myo-inositol diet led to cataract development, indicating that cataract development was not merely due to a nonspecific effect of SMIT overexpression. Introducing aldose reductase overexpressing transgene into heterozygous 3352 mice also led to cataract development, indicating that this type of cataract is primarily due to osmotic stress. CONCLUSIONS. The present results indicate that high levels of myo-inositol and sorbitol in the lens contribute to cataract development. This is a useful model to study the role of osmotic stress in cataractogenesis during lens development. (Invest Ophthalmol Vis Sci. 2000;41:1467-1472 C ataract is the most important cause of blindness in the world. Nearly 16 million people are estimated to be blind because of cataract. 1 There are a number of causes for cataract, including congenital cataract, cataract from infection, cataract from UV and X-ray irradiation and oxidation damage, and cataract associated with several diseases, particularly diabetes. The transparency in mammalian lenses is due to the presence of crystallin structures formed by highly ordered association of several proteins. Changes in ionic environment, a reduction in the level of antioxidants such as reduced glutathione and ascorbic acid, and changes in the level of other solutes may lead to random protein aggregation and disruption of the crystallin structures, resulting in lens opacity and cataract. Therefore, the lens needs to stabilize the intracellular osmotic pressure by regulating the influx and efflux of water, osmolytes, and other solutes. Osmotic stress due to the accumulation of sorbitol in the lens is most likely the cause of diabetic cataract. This is based on the fact that sorbitol accumulates to high levels in the lenses of diabetic animals 6 Development of lens opacity in vitro can be prevented by AR inhibitors or if the medium is made hypertonic to balance the increased sorbitol accumulation in the lens, indicating that osmotic stress is the cause of diabetic cataract. 9 To determine whether cataract caused by sorbitol accumulation is a consequence of osmotic stress rather than the toxic effect of sorbitol, we wanted to increase the lens myoinositol (MI) level to see if that also causes cataract. Myoinositol is one of the three major osmolytes in the lens besides sorbitol and taurine. 10 Influx of MI into lens is dependent on the Na ϩ -dependent MI transporter (SMIT). 11 In this study, we produced transgenic mice that overexpress SMIT constitutively in lens cells and found that they developed congenital cataract under normal rearing condition beginning at 2 to 8 weeks of age. These results provide strong evidence that a high level o
