title: Relative importance of aldose reductase versus nonenzymatic glycosylation on sugar cataract formation in diabetic rats.
abstract: The relative importance of sorbitol formation versus nonenzymatic glycosylation and advanced glycosylation end products (AGEs) on sugar cataract formation was examined in diabetic rats. Diabetes was experimentally induced in young, 50 g rats with streptozotocin, and aldose reductase inhibitors were administered in the diet for up to 8 weeks at concentrations of 0.06% for tolrestat or ponalrestat and 0.0125% for AL-1576. Cataract formation was monitored by hand-held slit lamp for up to 11 weeks. Lens polyol levels were monitored by GLC, glycosylated protein levels were spectrophotometrically determined, and AGE products were estimated by fluorescence measurements and ELISA. Sugar cataract formation was observed in all untreated diabetic rats while cataract formation was inhibited in all diabetic rats treated with the AR inhibitors. Lens sorbitol levels were reduced in all ARI-treated rats. Glycosylated lens protein levels were elevated in the diabetic rats, and these levels were not significantly lower in the non-cataractous lenses from ARI-treated diabetic rats. Fluorescence measurements of the lens proteins revealed increased lens AGE levels in all diabetic rats, and these were slightly reduced in the aldose reductase inhibitor treated diabetics. With ELISA, immunoreactive AGEs were only detected in cataractous lenses from the untreated diabetic rats. Immunoreactive AGEs were not detected in the clear lenses of the aldose reductase inhibitor treated diabetics or in the non-diabetic controls. These results support the concept that sugar cataract formation is initiated by the aldose reductase catalyzed intracellular accumulation of polyols and that these sugar cataracts can be prevented through inhibition of aldose reductase.
authors.affiliation: Laboratory of Ocular Therapeutics, National Eye Institute, NIH, Bethesda, Maryland 20892-1850, USA. kador@helix.nih.gov
authors.forename: P F
authors.initials: PF
authors.lastname: Kador
authors.forename: J W
authors.initials: JW
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Fujisawa
authors.forename: K
authors.initials: K
authors.lastname: Blessing
authors.forename: M F
authors.initials: MF
authors.lastname: Lou
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002386:Cataract / Q000201:enzymology* / Q000209:etiology; D003459:Crystallins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000209:etiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005449:Fluorenes / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006031:Glycosylation; D006827:Hydantoins / Q000494:pharmacology; D007908:Lens, Crystalline / Q000201:enzymology* / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000378:metabolism*; D013050:Spectrometry, Fluorescence
chemical_list: D003459:Crystallins; D004791:Enzyme Inhibitors; D005449:Fluorenes; D017127:Glycation End Products, Advanced; D006827:Hydantoins; D009281:Naphthalenes; D010793:Phthalazines; C052241:imirestat; C040550:tolrestat; C042829:ponalrestat; D013012:Sorbitol; D000449:Aldehyde Reductase; D005978:Glutathione