ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO2049

Cyclosporine A but Not Tacrolimus Promotes Pro-Apoptotic Endoplasmic Reticulum Stress in Cultured Kidney Cells

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Yilmaz, Duygu Elif, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Kirschner, Karin Michaela, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Demirci, Hasan, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Bachmann, Sebastian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Mutig, Kerim, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

Current immunosuppressive regimen in organ transplantation include calcineurin inhibitors (CNI), cyclosporine A (CsA) or tacrolimus (Tac), as the first-line therapy. Both CNI may produce renal side effects, which are typically stronger in patients receiving CsA. Sustained clinical demand for CsA requires improved understanding of mechanisms underlying its nephrotoxicity. CsA builds complexes with cyclophilins, whereas Tac recruits FKBP12 for calcineurin inhibition. We hypothesized that cytotoxic effects of CsA may be related with impaired chaperone function of cyclophilins resulting in endoplasmic reticulum (ER)-stress and pro-apoptotic unfolded protein response (UPR).

Methods

Effects of CsA vs. Tac (10 µM for 6 h) on the UPR signaling were compared in cultured native HEK293 cells, as well as in genetically modified cells lacking critical ER-stress sensors, PERK or ATF6. An established ER-stress inducer, thapsigargin (Tg) served as a positive control.

Results

CsA and Tg, but not Tac, induced ER-stress and UPR in native HEK293 cells, which was reflected by increased abundance of key UPR products (CHOP, spliced XBP1, and phosphorylated IRE1a). Furthermore, CsA but not Tac increased the abundance of caspase 3-(cCas3) suggesting stimulated apoptosis. Similar to CsA, knockdown of cyclophilin A or cyclophilin B using siRNA augmented CHOP and cCas3 levels. Deletion of PERK or ATF6 blunted the CsA-induced UPR. Furthermore, the CsA-dependent ER-stress was significantly reduced by concomitant application of chemical chaperones, TUDCA or 4-PBA.

Conclusion

In summary, these results suggest that renal side effects of CsA are partially mediated by suppression of cyclophilins, ER-stress, and pro-apoptotic UPR. Pharmacological modulation of UPR bears potential to alleviate the CsA nephrotoxicity.

Funding

  • Government Support – Non-U.S.