Inhibition of peptidyl-prolyl cis-trans isomerase B mediates cyclosporin A-induced apoptosis of islet beta cells

摘要

Cyclosporin A (CsA) is widely used as an immunosuppressor in the context of organ transplantation or autoimmune disorders. Recent studies have revealed the detrimental effects of CsA on insulin resistance and pancreatic beta cell failure; however, the molecular mechanisms are unknown. The present study sought to confirm the associations between CsA and beta cell failure, and to investigate the roles of proinsulin folding and endoplasmic reticulum (ER) stress in CsA-induced beta cell failure. The viability of MIN6 cells treated with CsA was evaluated with MTT assay. Expression levels of insulin, peptidyl-prolyl cis-trans isomerase B (PPIB), cleaved caspase-3, phospho-protein kinase R (PKR)-like endoplasmic reticulum kinase (p-PERK), PKR-like endoplasmic reticulum kinase (PERK), binding immunoglobulin protein (BIP), and C/EBP homologous protein (CHOP) were detected via reducing western blot assay. Non-reducing western blot analysis was performed to examine the expression of misfolded proinsulin peptides. The proliferation of MIN6 cells was not inhibited by CsA at concentrations 1 mu mol/l. CsA treatment resulted in the decreased expression of insulin and PPIB; however, it also increased the phosphorylation of PERK, and upregulated the expression of PERK, BIP, CHOP and cleaved caspase-3. The results indicated that CsA could induce pancreatic beta cell dysfunction and the potential mechanism underlying this phenomenon may be PPIB-associated proinsulin misfolding, which in turn induces ER stress in beta cells.