Autophagy protects renal tubular cells against cyclosporine toxicity

Autophagy. 2008 Aug;4(6):783-91. doi: 10.4161/auto.6477. Epub 2008 Jun 20.


A major side effect of the powerful immunosuppressive drug cyclosporine (CsA) is the development of a chronic nephrotoxicity whose mechanisms are not fully understood. Recent data suggest that tubular cells play a central role in the pathogenesis of chronic nephropathies. We have shown that CsA is responsible for endoplasmic reticulum (ER) stress in tubular cells. Autophagy has recently been described to be induced by ER stress and to alleviate its deleterious effects. In this study, we demonstrate that CsA induces autophagy in primary cultured human renal tubular cells through LC3II expression and autophagosomes visualization by electron microscopy. Autophagy is dependant on ER stress because various ER stress inducers activate autophagy, and salubrinal, an inhibitor of eIF2alpha dephosphorylation that protects cells against ER stress, inhibited LC3II expression. Furthermore, autophagy inhibition during CsA treatment with beclin1 siRNA significantly increases tubular cell death. Finally, immunohistochemical analysis of rat kidneys demonstrates a positive LC3 staining on injured tubular cells, suggesting that CsA induces autophagy in vivo. Taken together, these results demonstrate that CsA, through ER stress induction, activates autophagy as a protection against cell death.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / physiology*
  • Beclin-1
  • Biomarkers / metabolism
  • Cells, Cultured
  • Cyclosporine / toxicity*
  • Cytoprotection / drug effects*
  • Endoplasmic Reticulum / drug effects*
  • Enzyme Inhibitors / metabolism
  • Epithelial Cells* / cytology
  • Epithelial Cells* / drug effects
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunosuppressive Agents / toxicity*
  • Kidney Tubules / cytology*
  • Kidney Tubules / pathology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Thapsigargin / metabolism


  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Biomarkers
  • Enzyme Inhibitors
  • GRP78 protein, rat
  • Heat-Shock Proteins
  • Immunosuppressive Agents
  • Membrane Proteins
  • Molecular Chaperones
  • RNA, Small Interfering
  • Thapsigargin
  • Cyclosporine