Effects of trans-resveratrol on type 1 diabetes-induced inhibition of retinoic acid metabolism pathway in retinal pigment epithelium of Dark Agouti rats

Genesis and progression of diabetic retinopathy are due to glucotoxicity-induced changes in intracellular milieu in the retina. This study investigated effects of trans-resveratrol on type 1 diabetes-induced changes in gene expressions and retinoic acid metabolism pathway in the RPE (retinal pigment epithelium) of Dark Agouti rats. Microarray analysis showed differential expressions of 833 genes in the RPE of 14 day-long diabetic rats, which increased to 1249 after they received 5 mg/kg trans-resveratrol. Diabetes inhibited the expression of retinoic acid metabolism pathway genes- Lpl, Lrat, RPE65, Rdh5, Rdh10, Rdh12, Rlbp1 and Rbp1 and increased Crabp1. Trans-resveratrol further downregulated the expression of these genes except Lpl, Rdh5, and Rdh12 but upregulated Cyp26b1. RT-PCR showed inhibition of Lrat, Rdh5, and Rdh10 in diabetic rats supplemented with or without trans-resveratrol on 14d. Trans-resveratrol normalized Rdh5 and increased Lrat and Rdh10 transcriptions compared to control and diabetic rats. Trans-resveratrol amplified diabetes-induced inhibition of RPE65, but it inhibited the induced increase in Crabp1 transcription on 30d. Trans-resveratrol reversed the diabetes-induced decrease in Cyp26b1 transcription on 14d and 30d and normalized Cyp3a9 transcription on 30d. Trans-resveratrol normalized the diabetes-induced increase in Rdh5, Rdh10, and Cyp3a9 protein levels, but it further increased Cyp26b1 protein level. In conclusion, diabetes differentially regulates numerous genes in the RPE, including that of retinoic acid metabolism pathway. Trans-resveratrol supplementation is beneficial to normalize long-term effects, but not short-term effects, of diabetes on retinoic acid metabolism pathway in the RPE.