Sublethal heat shock and cyclosporine exposure produce tolerance against subsequent cyclosporine toxicity

Am J Physiol. 1996 Sep;271(3 Pt 2):F571-8. doi: 10.1152/ajprenal.1996.271.3.F571.


Sublethal heat shock has been shown to produce tolerance in cells and tissues subsequently exposed to heat or ischemia/ATP depletion. We tested whether heating LLC-PK1 cells for 2 h at 42 degrees C induced heat shock protein-70 (HSP-70) gene expression and conferred tolerance against subsequent cyclosporine A (CyA) toxicity. HSP-70 mRNA was increased immediately after heat shock, returning to baseline by 4 h. HSP-70 protein increased by 1 h after heat shock and declined thereafter, approaching baseline after 72 h. Cells heat shocked at 4 and 24 h prior to CyA exposure were significantly more viable than controls, at CyA concentrations near the median lethal dose (LD50). Cytoprotection declined with time after heat shock, concurrent with declining HSP-70 protein levels. Sublethal CyA exposure (50 micrograms/ml) for 24 h produced upregulation of HSP-70 mRNA and protein. Pretreatment with 50 micrograms/ml CyA for 24 h followed by exposure to a toxic concentration of CyA (200 micrograms/ml) produced significant cytoprotection compared with untreated controls. In conclusion, HSP-70 protein induction by sublethal heat shock or CyA exposure was associated with tolerance against subsequent lethal CyA exposure.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cyclosporine / poisoning*
  • Drug Tolerance
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Response / physiology*
  • Kidney Tubules / cytology
  • Kidney Tubules / drug effects*
  • LLC-PK1 Cells
  • RNA, Messenger / metabolism
  • Swine
  • Time Factors


  • HSP70 Heat-Shock Proteins
  • RNA, Messenger
  • Cyclosporine