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

Abstract

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 β cell failure; however, the molecular mechanisms are unknown. The present study sought to confirm the associations between CsA and β cell failure, and to investigate the roles of proinsulin folding and endoplasmic reticulum (ER) stress in CsA-induced β 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 μmol/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 β cell dysfunction and the potential mechanism underlying this phenomenon may be PPIB-associated proinsulin misfolding, which in turn induces ER stress in β cells.