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Cyclosporine-induced endoplasmic reticulum stress triggers tubular phenotypic changes and death

N Pallet1, N Bouvier, A Bendjallabah

  • 1INSERM U775, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France. nicolas.pallet@univ-paris5.fr

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
|September 13, 2008
PubMed

Insights

Cyclosporine causes kidney damage by inducing endoplasmic reticulum (ER) stress, leading to tubular cell dedifferentiation and death. Targeting ER stress may offer new therapies for cyclosporine-induced nephrotoxicity.

Area of Science:

  • Nephrology
  • Cell Biology
  • Toxicology

Background:

  • The mechanisms of cyclosporine-induced chronic nephrotoxicity are not fully understood.
  • Previous studies suggest cyclosporine may induce endoplasmic reticulum (ER) stress in kidney tubular cells.

Purpose of the Study:

  • To characterize tubular ER stress induced by cyclosporine.
  • To investigate the effects of ER stress on tubular cell differentiation and viability.
  • To explore potential therapeutic strategies targeting ER stress.

Main Methods:

  • Primary cultures of human tubular cells and in vivo rat models were used.
  • Cyclosporine and other ER stress inducers were applied to cells.
  • RNA interference targeting cyclophilin A was performed.
  • Salubrinal, an ER stress inhibitor, was used to assess protective effects.

Main Results:

  • Cyclosporine induced ER stress in vitro and in vivo.
  • ER stress led to epithelial phenotypic changes and protomyofibroblast generation, independent of TGF-β.
  • Inhibition of cyclophilin A mimicked ER stress and phenotypic changes.
  • Salubrinal reduced cyclosporine-induced phenotypic changes, cytotoxicity, and in vivo nephrotoxicity.

Conclusions:

  • Cyclosporine induces nephrotoxicity via a novel mechanism involving ER stress, leading to tubular cell dedifferentiation and death.
  • Targeting ER stress pathways presents a promising therapeutic approach for preventing cyclosporine-induced kidney damage.

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