PHARMACOLOGICAL PRECONDITIONING WITH LOW-DOSE CYCLOSPORINE OR FK506 REDUCES SUBSEQUENT ISCHEMIA/REPERFUSION INJURY IN RAT KIDNEY1,2

Abstract

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. 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). 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. 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.