Role of the polyol pathway in high glucose-induced apoptosis of retinal pericytes and proliferation of endothelial cells.

PURPOSE: The selective degeneration of pericytes and the proliferation of endothelial cells (ECs) appear to be associated with microaneurysm formation, an initial deficit in the early stage of diabetic retinopathy. The preventive effect of aldose reductase (AR) inhibitor (ARI) for high glucose-induced pericyte loss and EC growth was investigated. METHODS: The effect of high glucose (30 mM) exposure in the presence or absence of ARI for the cell growth of porcine pericytes and ECs was examined with the use of an in vitro coculture system to mimic the interaction between pericytes and ECs. To determine the role of transforming growth factor (TGF)-beta, its amount in culture media was measured, and the effects of the treatment of TGF-beta or neutralizing antibody on EC growth were examined. RESULTS: Abundant expression of AR and increased levels of polyol and apoptosis induced by high glucose were observed in pericytes, but not in ECs. ECs overexpressing AR cultured in high-glucose medium showed decreased cell viability. The growth-inhibitory effect of ECs on coculture with pericytes was attenuated by exposure to a high glucose concentration. Biochemical assays disclosed that the levels of active TGF-beta in media were linked to EC growth. Supply of active TGF-beta to coculture medium containing 30 mM D-glucose restored the inhibitory activity on EC growth. CONCLUSIONS: ARI rescued pericytes from high glucose-induced apoptosis and maintained the levels of TGF-beta, resulting in the prevention of cocultured EC growth.

Epithelial cell density in cataractous lenses of patients with diabetes: association with erythrocyte aldose reductase.

In the present study we evaluated the cell density of lens epithelium and its relation to the degree of erythrocyte aldose reductase (AR) in patients with type 2 diabetes. This prospective clinical study included 46 eyes of patients with type 2 diabetes and 48 eyes of patients without diabetes mellitus (DM). Flat preparations of lens epithelial cells (LECs) attached to the anterior capsule were studied. Multiple regression analysis was performed to evaluate the association between lens cell density and age, gender, type of cataract, duration of diabetes, diabetic retinopathy (DR), the levels of glycosylated hemoglobin (HbA1c) and erythrocyte AR. The mean density of LECs of patients with type 2 diabetes was 4,141+/-508cells/mm(2), which was significantly lower than that of patients without DM (4,560+/-458cells/mm(2); p<0.0001). Multiple regression analysis revealed that the level of erythrocyte AR was correlated with the reduction of LECs in the eyes of patients with type 2 diabetes. The correlation between the density of LECs and the amount of erythrocyte AR was significant in the diabetic group with a high value of HbA1c (>6.5%) or with DR. These results suggest that the polyol pathway via AR may be associated with the reduction of epithelial cell density in the eyes of patients with DM.