Pharmacological preconditioning with low-dose cyclosporine or FK506 reduces subsequent ischemia/reperfusion injury in rat kidney

Transplantation. 2001 Dec 15;72(11):1753-9. doi: 10.1097/00007890-200112150-00008.


Background: Ischemia/reperfusion (I/R) injury in the early posttransplant period is closely associated with delayed recovery of graft function, increased acute rejection, and late allograft dysfunction. Pharmacological preconditioning with low-dose cyclosporine (CsA) or FK506 was performed to induce ischemic tolerance in rat kidney with I/R injury.

Methods: Low-dose CsA (3 mg/kg, administered i.v.) or FK506 (0.3 mg/kg i.v.) were used to induce ischemic tolerance in Sprague-Dawley rats, and the induction of heat shock protein (hsp) 70 by CsA or FK506 was evaluated overtime. Rats were pretreated with CsA or FK506 6 hr before I/R injury when hsp70 was maximally expressed, and were killed 24 hr later. The effect of pharmacological preconditioning on subsequent I/R injury was evaluated in terms of renal function, histopathology score, assays for apoptosis (DNA fragmentation analysis, TUNEL staining, expressions of pro-apoptotic genes, and caspase activity), and the expression of inflammatory cytokine genes (interleukin-1 and tumor necrosis factor-alpha).

Results: Preconditioning with low-dose CsA or FK506 significantly improved renal function and renal histology, compared to rats with I/R injury. Apoptotic cell death (typical DNA laddering and increased TUNEL-positive cells) in rat kidneys with I/R injury, was decreased by pretreatment with low-dose CsA or FK506. Increased expression of pro-apoptotic genes (Fas, Fas-ligand, caspase 1 and 3) and activated caspases in ischemic rat kidneys were decreased after CsA or FK506 pretreatment.

Conclusions: Pretreatment with low-dose CsA or FK506 prevents subsequent I/R injury, and this effect may be related to the induction of hsp70. Pretreatment of renal donors with low-dose CsA or FK506 may result in an improvement in immediate posttransplant function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blood Urea Nitrogen
  • Caspases / metabolism
  • Creatinine / blood
  • Cyclosporine / administration & dosage*
  • Cyclosporine / therapeutic use
  • Dose-Response Relationship, Drug
  • Gene Expression / drug effects
  • HSP70 Heat-Shock Proteins / metabolism
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / therapeutic use
  • Interleukin-1 / metabolism
  • Ischemia / prevention & control*
  • Kidney Transplantation* / adverse effects*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Renal Circulation / drug effects*
  • Reperfusion Injury / prevention & control*
  • Tacrolimus / administration & dosage*
  • Tacrolimus / therapeutic use
  • Transplantation Conditioning* / methods*
  • Tumor Necrosis Factor-alpha / metabolism


  • HSP70 Heat-Shock Proteins
  • Immunosuppressive Agents
  • Interleukin-1
  • Tumor Necrosis Factor-alpha
  • Cyclosporine
  • Creatinine
  • Caspases
  • Tacrolimus