PURPOSE: Diabetic retinopathy (DR) is the most frequently occurring complication of diabetes. Alterations in ubiquitin-proteasome system (UPS) have been associated with several degenerative disorders. Hence, in this study, we investigated the status and role of UPS and ER stress in the retina of diabetic rats. METHODS: Diabetes was induced in rats by streptozotocin. Retinal markers, ER stress markers, components of UPS, ERAD, and autophagy were analyzed after 2- and 4-months of diabetes. Apoptosis was analyzed by TUNEL Assay. RESULTS: There were increased acellular capillaries and pericyte loss in diabetic rat retina. Decreased protein expression of UPS components - ubiquitin activating enzyme (E1), deubiquitinating enzymes (UCHL1 and UCHL5), SIAH1 (E3 ligase) and free ubiquitin were observed in the diabetic rats. Increased ER stress markers (ATF6, XBP1, and CHOP), decreased expression of HRD1, declined autophagy (LC3B) and increased apoptosis were observed in diabetic rats. Interestingly, treatment of diabetic rats with a chemical chaperone (4-PBA) restored the levels of DUBs and ameliorated ER stress-induced retinal cell death in type 1 diabetic rats. CONCLUSION: The declined UPS components: E1 and HRD1 in the retina of diabetic rats could elicit ER stress, and the prolonged ER stress may trigger CHOP-mediated neuronal apoptosis.
PURPOSE:Diabetic retinopathy (DR) is the most frequently occurring complication of diabetes. Alterations in ubiquitin-proteasome system (UPS) have been associated with several degenerative disorders. Hence, in this study, we investigated the status and role of UPS and ER stress in the retina of diabeticrats. METHODS:Diabetes was induced in rats by streptozotocin. Retinal markers, ER stress markers, components of UPS, ERAD, and autophagy were analyzed after 2- and 4-months of diabetes. Apoptosis was analyzed by TUNEL Assay. RESULTS: There were increased acellular capillaries and pericyte loss in diabeticrat retina. Decreased protein expression of UPS components - ubiquitin activating enzyme (E1), deubiquitinating enzymes (UCHL1 and UCHL5), SIAH1 (E3 ligase) and free ubiquitin were observed in the diabeticrats. Increased ER stress markers (ATF6, XBP1, and CHOP), decreased expression of HRD1, declined autophagy (LC3B) and increased apoptosis were observed in diabeticrats. Interestingly, treatment of diabeticrats with a chemical chaperone (4-PBA) restored the levels of DUBs and ameliorated ER stress-induced retinal cell death in type 1 diabeticrats. CONCLUSION: The declined UPS components: E1 and HRD1 in the retina of diabeticrats could elicit ER stress, and the prolonged ER stress may trigger CHOP-mediated neuronal apoptosis.
Authors: S Sreenivasa Reddy; Y K Prabhakar; Ch Uday Kumar; P Yadagiri Reddy; G Bhanuprakash Reddy Journal: Mol Vis Date: 2020-04-24 Impact factor: 2.367