Evaluation of an aldose reductase inhibitor on lens metabolism, ATPases and antioxidative defense in streptozotocin-diabetic rats: an intervention study.
OBJECTIVE
Aldose reductase inhibitors (ARIs) prevent biochemical abnormalities associated with diabetic complications. We evaluated whether a short-term intervention with an adequate dose of ARI, introduced at the very early, precataractous stage, reversed diabetes-induced metabolic imbalances, down-regulation of ATPases and oxidative stress in the lens. Methods. The groups included mature control and streptozotocin-diabetic rats treated with or without ARI sorbinil (65 mg x kg(-1) x day(-1), in the diet, for 2 weeks after 4 weeks of untreated diabetes). Free cytosolic NAD+:NADH and NADP+:NADPH ratios were calculated from the lactate dehydrogenase and malic enzyme systems. Concentrations of metabolites and adenine nucleotides, Na+/K+-ATPase, H+-ATPase and Ca++-independent Mg++-ATPase activities and variables of oxidative stress were measured in individual lenses. Results. Sorbinil treatment essentially corrected diabetes-induced sorbitol and fructose accumulation, myo-inositol depletion, decrease in free cytosolic NAD+:NADH ratio and energy deficiency. Malondialdehyde accumulation, reduced glutathione depletion and the increase in oxidized glutathione:reduced glutathione ratio were partially corrected. Free cytosolic NADP+:NADPH ratio and 4-hydroxyalkenal concentrations were similarly increased in diabetic rats treated with or without ARI. Sorbinil did not counteract diabetes-induced down-regulation of the three ATPase activities.


CONCLUSIONS
All biochemical changes assessed in our study are known to be prevented by ARIs. Despite the essential normalization of the sorbitol pathway activity, only part of them were, however, reversed by the ARI treatment introduced at the very early, i.e. precataractous, stage of diabetes. Therefore, intervention studies can easily underestimate the importance of aldose reductase in the pathogenesis of diabetic complications and should be interpreted with caution.
Obrosova
I G
IG
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0354, USA.
Fathallah
L
L
D000227:Adenine Nucleotides / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007294:Inositol / Q000378:metabolism; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism
D000227:Adenine Nucleotides; D000975:Antioxidants; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D009243:NAD; D005632:Fructose; D007294:Inositol; D013012:Sorbitol; D009249:NADP; D000449:Aldehyde Reductase; D000251:Adenosine Triphosphatases; D017301:Ca(2+) Mg(2+)-ATPase; D006180:Proton-Translocating ATPases; D000254:Sodium-Potassium-Exchanging ATPase; C026411:sorbinil; D005947:Glucose