Aldose Reductase Inhibitor Fidarestat Prevents Diabetic Ocular Complications in Spontaneously Diabetic Torii Rats

Abstract

We evaluated the effect of an aldose reductase inhibitor, fidarestat, on diabetic retinopathy (DR) and cataract in spontaneously diabetic Torii (SDT) rats. Four rat groups were included: untreated, low- and high-dose (8 and 32 mg/kg/day) fidarestat-treated SDT rats, and nondiabetic control Sprague-Dawley rats. DR and cataract were evaluated and retinal and lens sorbitol, reduced glutathione (GSH), ocular fluid vascular endothelial growth factor (VEGF), and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured. The incidence rates of DR and cataract were significantly lower in the low- and high-dose fidarestat groups vs the untreated group (p<0.001/p<0.001). Retinal and lens sorbitol levels were lower in the control (1.1±0.1/3.1±0.2 nmol/mg protein) (p<0.05/p<0.01) and low- (2.7±1.1/30.0±3.3 nmol/mg protein) (p<0.01/p<0.01) and high-dose groups (0.7±0.2/5.9±0.6 nmol/mg protein) (p<0.001/p<0.001) vs the untreated group (23.2±4.7/123.9±29.6 nmol/mg protein). Retinal and lens GSH levels were higher in the nondiabetic control (52.2±5.8/29.0±2.7 � mol/mg protein) (p<0.01/p<0.001) and the low- (46.8±8.2/24.7±2.8 � mol/mg protein) (not significant (NS)/p<0.001) and high-dose groups (63.3±14.6/26.9±3.6 � mol/mg protein) (p<0.05/p<0.001) vs the untreated group (30.3±2.0/1.6±0.4 � mol/mg protein). VEGF levels were lower in the nondiabetic control (40.4±10.0 pg/ml) (p<0.01) and low- (65.3±4.5 pg/ml) (p<0.05) and high-dose groups (47.7±10 pg/ml) (p<0.001) vs the untreated group (324.7±76.4 pg/ml). 8-OHdG levels were lower in the nondiabetic control (0.73±0.11 ng/mg creatinine) (p<0.01) and low- (4.57±0.42 ng/mg creatinine) (NS) and high-dose groups (3.58±0.70 ng/mg creatinine) (NS) vs the untreated group (6.04±1.28 ng/ml). Fidarestat inhibited activation of the polyol pathway, reduced oxidative stress and VEGF, and prevented DR and cataract in SDT rats.