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Hyperglycemia Promotes Mitophagy and Thereby Mitigates Hyperglycemia-Induced Damage

Published:September 02, 2022DOI:https://doi.org/10.1016/j.ajpath.2022.08.004
      The observation that diabetic retinopathy (DR) typically takes decades to develop suggests the existence of an endogenous system that protects from diabetes-induced damage. To investigate if such a system exists in primary human retinal endothelial cells, we cultured them in either normal glucose (5 mmol/L) or high glucose (30 mmol/L; HG). We observed that prolonged exposure to HG was beneficial instead of detrimental. Although tumor necrosis factor-α–induced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 was unaffected after 1 day of HG, it waned as the exposure to HG was extended. Similarly, oxidative stress–induced death decreased as exposure to HG was prolonged. Furthermore, mitochondrial functionality, which was compromised by 1 day of HG, was improved by 10 days of HG, and this change required increased clearance of damaged mitochondria (mitophagy). Finally, antagonizing mitochondrial dynamics compromised the cells' ability to endure HG: susceptibility to cell death increased, and basal barrier function and responsiveness to vascular endothelial growth factor deteriorated. These observations indicate the existence of an endogenous system that protects human retinal endothelial cells from the deleterious effects of HG. Hyperglycemia-induced mitochondrial adaptation is a plausible contributor to the mechanism responsible for the delayed onset of DR; loss of hyperglycemia-induced mitochondrial adaptation may set the stage for the development of DR.
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