Intermittent but not constant high glucose induces ER stress and inflammation in human retinal pericytes

Diabetic retinopathy is a chronic inflammatory disease characterized by vascular damage and neuronal degeneration. Previously, we reported that activated retinal pericytes secret high levels of proinflammatory cytokines, such as macrophage chemoattractant protein 1 (MCP-1), and may play a pivotal role in macrophage recruitment and inflammatory retinal damage. However, the mechanism underlying diabetes-induced pericyte inflammation remains poorly understood. In the present study, we evaluated the effects of constant and intermittent high glucose on inflammatory cytokine production in human retinal pericytes (HRP) and explored the role of endoplasmic reticulum (ER) stress in pericyte inflammation. We found that intermittent high glucose, but not constant high glucose, increases MCP-1 secretion and expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key mediators of ER stress-associated inflammation and cell death. Inhibition of ER stress by chemical chaperones successfully prevented glucose fluctuation-induced ATF4/CHOP activation and inflammatory cytokine production. Our results suggest that activation of ER stress by glucose fluctuation may play a causal role in pericyte injury and inflammation in diabetic retinopathy.