Cellular osmolytes reduce lens epithelial cell death andalleviate cataract formation in galactosemic rats

[摘要] Purpose: Many cataractogenic stresses also induce endoplasmicreticulum (ER) stress in lens epithelial cells (LECs), which appears tobe one of the universal inducers of cell death. In galactosemic rats,activation of ER stress results in the activation of the unfoldedprotein response (UPR)-dependent death pathway, production of reactiveoxygen species (ROS), and cell death. All are induced and precedecataract formation. Cellular osmolytes such as 4-phenylbutyric acid(PBA), trimethylamine N-oxide (TMAO), and tauroursodeoxychoric acid(TUDCA) are known to suppress the induction of ER stress. Weinvestigated whether these small molecules prevent cataract formation ingalactose-fed rat lenses.Methods: Cultured LECs were treated with galactose and each cellularosmolyte. Sprague-Dawley rats were fed a 50% galactose chow for 15 dayswith or without cellular osmolyte treatment. Similarly, selenite wasinjected subcutaneously into rats with or without cellular osmolytes.Calcein AM and ethidium homodimer-1 (EthD) were used to detect live anddead cells, respectively. The cellular osmolytes, PBA, TMAO, and TUDCAwere tested for their ability to suppress LEC death and cataractformation.Results: Cellular osmolytes rescued cultured human LECs which weretreated with the ER stressors. We administered these osmolytes eitherorally or by injection into galactosemic Sprague-Dawley rats. These ratshad significantly reduced LEC death and partially delayed hypermaturecataract formation. Since the UPR was not activated in cultured LECstreated with selenite, we used the selenite nuclear cataract as aUPR-independent death pathway control. In selenite-induced nuclearcataract in rats, cellular osmolytes did not prevent LEC death and didnot alleviate cataract formation.Conclusions: These results further establish that ER stress and LECdeath play a vital role in certain types of cataract formation. Inaddition, cellular osmolytes may be potential prophylactic drugs forsome types of cataracts.

[学科分类] 生物化学/生物物理