Abstract
This study investigates whether reduced optic atrophy 1 (Opa1) level promotes apoptosis and retinal vascular lesions associated with diabetic retinopathy (DR). Four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Opa1+/− mice, and diabetic Opa1+/− mice were used in this study. 16 weeks after diabetes onset, retinas were assessed for Opa1 and Bax levels by Western blot analysis, and retinal networks were examined for acellular capillaries (AC) and pericyte loss (PL). Apoptotic cells were detected in retinal capillaries using TUNEL assay, and caspase-3 activity was assessed using fluorometric analysis. Opa1 expression was significantly downregulated in retinas of diabetic and Opa1+/− mice compared with those of WT mice. Inducing diabetes further decreased Opa1 expression in retinas of Opa1+/− mice. Increased cytochrome c release concomitant with increased level of pro-apoptotic Bax and elevated caspase-3 activity were observed in retinas of diabetic and Opa1+/− mice; the number of TUNEL-positive cells and AC/PL was also significantly increased. An additional decrease in the Opa1 level in retinas of diabetic Opa1+/− mice exacerbated the development of apoptotic cells and AC/PL compared with those of diabetic mice. Diabetes-induced Opa1 downregulation contributes, at least in part, to the development of retinal vascular lesions characteristic of DR.
Highlights
We have shown that a diabetes-induced decrease in retinal optic atrophy 1 (Opa1) levels pr and that commitment to cell death is regulated downstream of cytochrome c release [28,29,30]
It is of interest that reduced Opa1 level alone in the Opa1+/− was micesuffiwas cient to yield similar vascular changes seenseen in retinas of diabetic animals
In the type 2 diabetic mouse model, db/db mice, Opa1 levels were significantly reduced in mitochondria of pancreatic islets compared with those of non-diabetic mice [35]. These findings indicate that high glucose (HG)- or diabetes-induced Opa1 downregulation could result in significant negative consequences related to diabetic complications
Summary
Loss of retinal vascular cells is a prominent characteristic lesion in early DR [1,2], one of the leading causes of blindness in working-age adults [3]. It has become increasingly evident that mitochondrial abnormalities play a central role in contributing to the pathogenesis of DR [4,5,6,7,8,9,10,11,12,13,14,15,16]. High glucose (HG)- or diabetes-induced alteration to mitochondrial morphology has been shown to promote apoptotic cell death [4,7,8,10,11,12,13,14,15,16,17]
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