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J. Zhang, M. Widness, T.S. Kern; Captopril Inhibits Retinal Glucose Accumulation and High Glucose-induced Increase in Glucose Transport in Retinal Endothelial Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3570.
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Purpose: Clinical studies have detected an unexpected inhibition of diabetic retinopathy by ACE (angiotensin-converting enzyme) inhibitors, and the mechanism for this action is unclear. In light of evidence indicating that the severity of hyperglycemia is a major initiating factor in the pathogenesis of the retinopathy, we examined the effect of ACE inhibitors on glucose accumulation in retinas of diabetic rats and on glucose transport in retinal endothelial cells cultured in elevated glucose concentration. Methods: Rats were made experimentally diabetic by injection of streptozotocin and treated with captopril (25 mg/kg body weight/day) for 8 weeks. Bovine retinal endothelial cells were cultured in the medium containing either 5.5 mM or 25 mM of glucose and treated with different concentrations of captopril for 5 days. Glucose content in retinas and cultured cells was measured spectrometrically. Expression of GLUT1 glucose transporter in retinas and cultured cells was determined by Western blotting. Glucose uptake was carried out by using 3-O-methyl-D-[3H]glucose. Results: Treatment of rats with captopril inhibited the diabetes-induced accumulation of glucose in the retina by 48% (p<0.01) compared to diabetes control. Likewise, captopril significantly inhibited intracellular accumulation of glucose in primary bovine retinal endothelial cells cultured in elevated glucose concentration, indicating that the captopril-induced inhibition of glucose accumulation observed in retinal tissue of diabetic rats was not due solely to reduction in blood pressure or in vascular permeability. Although it had no effect in expression of the GLUT1 glucose transporter in retinas and cultured retinal endothelial cells, captopril at concentration of 2 mM significantly inhibited high glucose-induced increase in GLUT1-mediated glucose transport in cultured retinal endothelial cells by 67±10%. In addition, the elevated glucose concentration caused a dramatic decrease in AMP-activated protein kinase activity in retinal endothelial cells and retinal Muller cells and captopril corrected this abnormality. Conclusions: Our data suggest that inhibitory effect of captopril on intracellular accumulation of glucose is due in part to decreased glucose transport, and that activation of AMP-activated protein kinase may be involved in this process. Inhibition of glucose accumulation within retinal cells likely contributes at least in part to the observed inhibition of diabetic retinopathy by ACE inhibitors.
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