Pharmacological preconditioning with low-dose cyclosporine or FK506 reduces subsequent ischemia/reperfusion injury in rat kidney.
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.
Yang
C W
CW
Department of Internal Medicine, Kangnam St. Mary's Hospital, The Catholic University of Korea, 505 Banpo-Dong, Seocho-Ku, Seoul, 137-040, Korea.
Ahn
H J
HJ
Han
H J
HJ
Kim
W Y
WY
Li
C
C
Shin
M J
MJ
Kim
S K
SK
Park
J H
JH
Kim
Y S
YS
Moon
I S
IS
Bang
B K
BK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001806:Blood Urea Nitrogen; D020169:Caspases / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007375:Interleukin-1 / Q000378:metabolism; D007511:Ischemia / Q000517:prevention & control*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*; D015427:Reperfusion Injury / Q000517:prevention & control*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000627:therapeutic use; D019172:Transplantation Conditioning / Q000379:methods*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D003404:Creatinine; D020169:Caspases; D016559:Tacrolimus