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Enhancement of P2X₇-Induced Pore Formation and Apoptosis: An Early Effect of Diabetes on the Retinal Microvasculature

¹From the Departments of Ophthalmology and Visual Sciences and ²Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.

PURPOSE. A sight-threatening complication of diabetes is cell death in retinal capillaries. Currently, the mechanisms responsible for this classic manifestation of diabetic retinopathy remain uncertain. The hypothesis for the current study is that diabetes increases the vulnerability of retinal microvessels to the potentially lethal consequences of having their P2X₇ purinoceptors activated. A pathophysiological role is suspected for these receptor-operated channels because, in addition to transducing retinovascular responses to extracellular adenosine triphosphate (ATP), the sustained opening of these channels can induce the formation of large transmembrane pores.

METHODS. In pericyte-containing retinal microvessels that were freshly isolated from nondiabetic and streptozotocin-injected rats, cells with pores were identified by the uptake of YO-PRO-1. Cell viability was assayed by trypan blue dye exclusion, and cleaved caspase-3 immunoreactivity, TUNEL positivity, and nuclear morphology were used to detect apoptotic cells. Patch-clamp recordings assessed electrophysiological parameters.

RESULTS. Activation of P2X₇ receptors caused large pores to form and apoptosis to occur in retinal capillaries of nondiabetic and diabetic rats. Of importance to diabetes, the agonist concentration needed to open pores and trigger apoptosis decreased markedly soon after the onset of streptozotocin-induced hyperglycemia. However, despite this increased sensitivity, diabetes minimally affected the P2X₇-induced ionic currents. Thus, rather than upregulate the number of functional P2X₇ receptor/channels, diabetes appears to facilitate the channel-to-pore transition that occurs during activation of these purinoceptors. In this way, normally nonlethal concentrations of P2X₇ ligands may trigger apoptosis in microvessels of the diabetic retina.

CONCLUSIONS. A diabetes-induced increase in the vulnerability of retinal microvessels to the lethal effect of P2X₇ receptor activation may be a previously unrecognized mechanism by which diabetic retinopathy progresses.

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