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Abstract: PO2387

Immunosuppression by Cyclosporine A Affects Proximal Tubular Homeostasis via Endoplasmic Reticulum Stress

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Popovic, Suncica, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Hu, Junda, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Demirci, Hasan, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Yilmaz, Duygu Elif, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Dittmayer, Carsten, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Xu, Yan, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Thomson, Martin N., Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Mutig, Kerim, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Bachmann, Sebastian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

Calcineurin inhibitors (CNI) such as cyclosporine A (CsA) or tacrolimus are first-line immunosuppressive drugs used after solid organ transplantation. However, renal side effects such as vascular and tubulo-interstitial malformations regularly occur in their long-term usage, especially in patients with renal allografts. Measures to reduce CNI nephrotoxicity by RAS inhibition or calcium antagonism had limited success. Dysfunctions in renal epithelial proteostasis suggested CNI-induced ER stress and malfunction of the unfolded protein response (UPR).

Methods

We have established a rat model for chronic CNI nephrotoxicity to test whether epithelial pathology and loss of functioning nephrons are related to ER stress and UPR dysfunction. Adult male Wistar rats received cyclosporin A (CsA, 25 to 40 mg/kg. b.w.) or vehicle via subcutaneously implanted minipumps. After three weeks, rats were sacrificed and organs removed for protein analysis or perfusion-fixed and kidneys analyzed for histopathology.

Results

Rats with CsA displayed a stimulated RAS and increased distal NaCl transporter activity along with decreased urine volume, GFR, FENa, and COX-2 expression. Pathological changes in vasculature and glomeruli were inconspicuous, whereas early proximal tubular segments (S1, S2) revealed large lysosomal vacuoles with granular content, their abundance correlating with epithelial dedifferentiation, basement membrane thickening, and subepithelial collagen I accumulation. Protein endocytosis was diminished. Changes in UPR included enhanced peIF2a, pPERK, CHOP, and BiP levels. Parallel studies in cultured cells indicated sensitivity to chemical chaperones ameliorating proteostasis.

Conclusion

These results suggest a so far unrecognized role of proximal tubular homeostasis in long term CsA-induced nephrotoxicity. Addressing UPR failure and restitution of proteostasis in proximal tubule may, therefore, have renoprotective potential.

Funding

  • Government Support - Non-U.S.