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.
Highlights
Diabetic retinopathy (DR), cataracts, and neovascular glaucoma are three major vision-threatening diabetic ocular complications
We evaluated the effect of an aldose reductase inhibitor, fidarestat, on diabetic retinopathy (DR) and cataract in spontaneously diabetic Torii (SDT) rats
Fidarestat had no significant effect on body weight among the three groups of SDT rats
Summary
Diabetic retinopathy (DR), cataracts, and neovascular glaucoma are three major vision-threatening diabetic ocular complications. Cataract can be treated surgically, DR eventually progresses to proliferative DR (PDR) accompanied by tractional retinal detachment and/or neovascular glaucoma. PDR and neovascular glaucoma can be treated by laser and vitreous surgery in certain cases, but the postoperative visual function is usually unsatisfactory. Prevention of DR is ideal for preventing blindness in patients with diabetes. Clinical trials have shown that intensive glycemic control reduces the incidence and progression of DR [1,2,3]. Achieving normal glucose homeostasis is not accomplished even in patients who are highly compliant. DR continues to develop and progress in well-controlled patients [1,2,3]
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