Cyclic Stretch–Induced Reactive Oxygen Species Generation Enhances Apoptosis in Retinal Pericytes Through c-Jun NH 2 -Terminal Kinase Activation

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Abstract
Hypertension is known to exacerbate diabetic complications, such as retinopathy and nephropathy. Apoptosis of retinal vascular pericytes has been well established as the earliest conceivable change in diabetic retinopathy. In this study, we investigated the contribution of cyclic stretch, which mimics a hypertensive state to pericyte apoptosis. A 48-hour cyclic stretch induced DNA fragmentation in porcine retinal pericytes and increased the number of TUNEL+ cells at a pathophysiologically relevant extension level (10%/60 cycles per minute). Stretch also increased intracellular reactive oxygen species generation and increased c-Jun NH 2 -terminal kinase phosphorylation in a time- and magnitude-dependent manner, which were reduced by the nicotinamide-adenine dinucleotide phosphate oxidase inhibitor diphenylene iodonium or dominant-negative protein kinase C-δ. Stretch activated protein kinase C-δ and increased its association with p47phox. Stretch induced cleavage of caspase-9 and -3 and increased caspase-3 activity. Protein kinase C-δ or c-Jun NH 2 -terminal kinase inhibition normalized stretch-induced caspase-3 activity and prevented stretch-induced apoptosis. These data indicate that cyclic stretch induces apoptosis in porcine retinal pericytes by activation of the reactive oxygen species–c-Jun NH 2 -terminal kinase–caspase cascades, suggesting a novel molecular mechanism to explain the exacerbation of early diabetic retinopathy by concomitant hypertension.

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