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Hiroyoshi Kawada, Zifeng Zhang, Peng Zhang, James Randazzo, Peter F. Kador; Comparative Studies Of High Hexose-induced Changes In Growth Factors And Mapk Signaling Of Rat Lenses In Vivo And In Vitro. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2788.
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© ARVO (1962-2015); The Authors (2016-present)
Formation of sugar cataracts is linked to the aldose reductase (AR) catalyzed accumulation of sugar alcohols (polyols). In addition, AR activity has also been linked to signal transduction changes, cytotoxic signals and activation of apoptosis. The purpose of this study was to investigate the links between AR activity, polyol formation, osmotic changes and cell signaling changes in intact rat lenses cultured under high glucose/galactose conditions compared to similar changes in lenses from rats with diabetes mellitus/galactosemia.
For the in vivo studies, lenses were obtained from streptozotocin-induced diabetic Sprague Dawley rats who were fed diet with/without the aldose reductase inhibitors AL1576 or tolrestat for 10 weeks. Similar rats were also fed a 50% galactose diet with/without AL1576. For the in vitro studies, lenses from non-diabetic Sprague Dawley rats were cultured for up to 48 hrs in TC-199-bicarbonate media containing either 30 mM fructose (control), or 30 mM glucose or galactose with/without the AR inhibitors AL1576 or tolrestat, or the sorbitol dehydrogenase inhibitor CP-470,711, or 30 mM mannitol (osmotic-compensated media). GSH was spectrophotometrically measured using the DTNB method. Sorbitol levels were measured by HPLC. Growth factors and transduction pathways were measured by Western blots using the antibodies basic-FGF, IGF-1, TGF-β, P-ERK1/2, P-SAPK/JNK, and P-Akt.
GSH was lowered in lenses cultured in high glucose/galactose media and in lenses from untreated diabetic and galactose-fed rats. GSH loss was lessened by ARI treatment. Lenses from diabetic/galactosemic rats or from high glucose and galactose cultured conditions showed increased expression of basic-FGF, IGF-1, TGF-β, P-Akt, P-ERK1/2 and P-SAPK/JNK while treatment with ARIs normalized the expression to that of normal control rats. Culturing the rat lenses in osmotic-compensated media containing 30 mM mannitol also resulted in normal expression of growth factors and signaling components.
These studies suggest that polyol-linked osmotic changes preceede growth factor and signaling expression changes observed during sugar cataract formation.
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