P2X7 receptor activation participates in high glucose‐induced caspase‐1 activation

Hyperglycemia leads to sustained activation of caspase‐1 in the retinas of diabetic animals and patients in vivo and in retinal Müller cells in vitro . How this caspase‐1 activation is achieved is unknown. Activation of P2X7 receptors (P2X7R) by ATP is known to induce inflammasome assembly; a step required for caspase‐1 activation. P2X7R are upregulated in fibroblasts of diabetic patients leading to speculation that increased activation may also occur in diabetic retinas. However, P2X7R regulation of caspase‐1 has predominately been characterized in macrophages primed with microbial mediators but not in sterile inflammation. We have characterized the effects of elevated glucose and nucleotides on P2X7R and caspase‐1 activation. Transformed rat Müller cells (rMC‐1) were treated in the presence of normal or high glucose plus ATP, UTP, or ADP (10μM‐10mM) and with or without the P2X7R antagonist, A438079 (10–20μM) prior to assay of caspase‐1 activity. qPCR was performed for P2X7R on cDNA from rMC‐1 following treatment. Data indicate high glucose induces increased accumulation of P2X7R mRNA. Treatment with ATP, but not UTP or ADP, increased caspase‐1 activity in the presence or absence of high glucose and these increases were attenuated by A438079 . These data suggest that P2X7R activation may play a role in mediating hyperglycemia induced caspase‐1 activation and the secretion of IL‐1β that drives diabetic retinopathy. Supported by: T32‐EY07157, EY017206 , GM36387, 7‐06‐RA‐95