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M. Mulhern, C. J. Madson, P. F. Kador, T. Shinohara; Chemical Chaperones Suppress ER Stress, LEC Death, and Cataract Formation in the Galactosemic Rat Lens. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3185.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetes induces a number of ocular complications including cataract. Diabetic complications can induce endoplasmic reticulum (ER) stress which damages lens epithelial cells (LECs) and results in cataract formation. Chemical chaperones such as 4-phenyl butyric acid (PBA), trimethylamine N-oxide dihydrate (TMAO), and tauroursodeoxycholic acid (TUDCA) are known to suppress ER stress. All 3 of these chaperones 1) improve ER folding capacity, 2) stabilize protein conformation, and 3) facilitate the trafficking of misfolded proteins and promote cell survival. The purpose of this study was to investigate whether these chemical chaperones can be used as therapeutic agents to suppress LEC death and the subsequent development of cataract in galactosemic rats.
Sprague-Dawley rats were fed a chow containing 50% galactose. 250-500 mg of chemical chaperones were administered twice a day by gavage, subcutaneous injection, and interperitonial injection. Calcein and ethidium homodimer-1 (EthD-1) staining were used to evaluate live and dead cells. Protein blot analysis was used to identify the UPR specific proteins. Dichlorodihydrofluorescein diacetate (DCF) was used to evaluate levels of reactive oxygen species (ROS).
Increased levels of the UPR specific proteins Bip/GRP78, CHOP, and LEDGF were detected along with the production of ROS and apoptosis in the LECs from galactosemic rat lenses. The UPR was only observed in lens epithelial cells and not fiber cells. Treating the galactose-fed rats with chemical chaperones suppressed LEC mortality and subsequent cataract formation but not lens hydration.
ER stress appears to play a vital role in cataract formation in galactose-fed rats. Nontoxic chemical chaperones are able to suppress LEC death and subsequently delay cataract formation in these rats. Modulating the UPR pathway by chemical chaperones may offer a novel therapeutic approach for ER-induced cataract.
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