Das Immunsuppressivum Cyclosporin A verursacht Stress im endoplasmatischen Retikulum und Apoptose in Nierenepithelzellen durch Hemmung der Cyclophilinaktivität ; Immunosuppressant cyclosporine A induces endoplasmic reticulum stress and apoptosis in kidney epithelial cells due to suppression of cyclophilin activity

Calcineurin inhibitors (CNI) such as cyclosporine A (CsA) and tacrolimus (Tac), are widely-used as immunosuppressants after solid organ transplantations to prevent allo-graft rejection. However, their therapeutic benefits are limited by nephrotoxicity. In particular, CsA is associated with greater nephrotoxicity than Tac. CNI inhibit calcineurin indirectly by building complexes with different immunophilins: CsA binds to cyclophilins and Tac interacts with the FK506-binding protein (FKBP). These complexes then bind to and inhibit calcineurin. We hypothesized that the stronger nephrotoxicity of CsA may be as-sociated with suppression of cyclophilins, whose chaperone function is crucial in proteo-stasis. Imbalanced proteostasis may lead to endoplasmic reticulum (ER) stress and mal-adaptive unfolded protein response (UPR) in kidney epithelia. To this end, the effects of CsA and Tac treatment (10 μM, for 6 hours each) on UPR and apoptosis markers were evaluated in human embryonic kidney 293 (HEK 293) cells, primary human renal proximal tubular epithelial cells (HRPTEpC) and freshly isolated rat proximal tubules (PT). CsA treatment in cultured cells and isolated PTs induced significant increases to the levels of UPR and proapoptotic markers, whereas Tac treatment resulted in either mild or no effect. Knockdown of cyclophilin A (CYPA) or cyclophilin B (CYPB) via small interfering RNA (siRNA) stimulated proapoptotic UPR and apoptosis, similar to CsA treatment. Concom-itant application of the chemical chaperones tauroursodeoxycholic acid (TUDCA) or 4-phenylbutyric acid (4-PBA) alleviated CsA-induced ER stress and UPR. Similarly, inacti-vation of critical UPR pathways by CRISPR/Cas9 mediated deletion of protein kinase RNA-like ER kinase (PERK) or activating transcription factor 6 (ATF6) in HEK 293 cells also blunted CsA-induced UPR. In summary, CsA induces stronger expression of UPR and proapoptic markers than Tac, which suggests that higher nephrotoxicity associated with CsA treatment may be, at least in part, derived ...