PKC beta Inhibition Promotes TXNIP Degradation to Ameliorate Pancreatic beta-Cell Dysfunction
PHARMACOLOGY(2022)
Abstract
Introduction: Pancreatic beta-cell dysfunction is largely regulated by TXNIP accumulation, we have previously disclosed the role of PKA in TXNIP degradation during beta-cell dysfunction. However, whether other kinases (PKCs) still regulate TXNIP is unclear, which is beneficial to alleviate beta-cell dysfunction. Methods: Thapsigargin (ER stress inducer) was used to induce beta-cell dysfunction. PKC's inhibitors were screened by Western blotting indicated by TXNIP. Also RT-qPCR and Co-immunoprecipitation were applied for evaluating the beta-cell improvement ability of PKC's inhibitors, and the insulin secretion ability was evaluated by glucose-stimulated insulin secretion assay. Results: PKC's pan-inhibitor, Ro31-8220, decreased beta-cell apoptosis and improved insulin secretion under ER stress or high glucose (HG) conditions. Further studies showed that Ro31-8220 reduced ER stress or HG-induced TXNIP levels. On the other side, PKC beta activation or overexpression could reverse the effect of Ro31-8220 on TXNIP. Also, PKC beta selective inhibitor, ruboxistaurin, induced TXNIP degradation as significantly as Ro31-8220 did. Conclusion: This study reveals the regulating mechanism of PKC beta inhibitor on TXNIP degradation to improve beta-cell dysfunction. These data indicated PKC beta inhibitor is a promising agent for ameliorating beta-cell dysfunction through TXNIP.
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Key words
PKC beta, Ro31-8220, Type 2 diabetes, TXNIP, beta-Cell
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