Prevention of cold ischaemia-reperfusion injury by an endothelin receptor antagonist in experimental renal transplantation

Endothelin (ET) is known to play a role in the pathogenesis of warm ischaemic renal damage, however, little is known about its involvement in renal cold ischaemia. This study was designed to investigate the response of ET after kidney cold ischaemia, and to assess the potential protective effect of bosentan, a dual, non-selective ET(A)/ET(B) receptor antagonist, against cold ischaemia reperfusion injury in a rat model of syngeneic renal transplantation. Kidneys from Lewis rats were transplanted, either immediately or after 5 h of cold preservation. After 48 h, contralateral nephrectomy was performed. Rats were organized into three groups: Tr-NoISC, no cold ischaemia; Tr-ISC, 5 h cold ischaemia; and Tr-BOS, 5 h cold ischaemia plus bosentan (100 mg/kg/day, from the day before transplantation until the seventh day post-transplantation). On day 7, plasma and tissue immunoreactive ET (irET), as well as ET mRNA tissue expression, were evaluated. Renal function was measured by means of serum creatinine on days 3, 4, 5 and 7, and by creatinine clearance on day 7. Conventional histology was performed. The ischaemic group had significantly higher plasma irET levels than the non-ischaemic group and significantly lower levels than the bosentan group. Tissue irET levels and ET mRNA expression were similar in the ischaemic and bosentan groups and were higher than in the non-ischaemic group. Throughout the follow-up, serum creatinine was significantly higher in the ischaemic group than in the bosentan group. Moreover, creatinine decreased rapidly in the bosentan group after nephrectomy, whereas it continued to increase for 48 h in the ischaemic group. Kidneys from the ischaemic group showed a higher degree of tubular-cell necrosis and epithelial-cell detachment than kidneys from the bosentan group. We conclude that cold ischaemia and preservation damage induces an increase in renal ET mRNA and irET expression in the reperfusion phase, contributing both to the deterioration of renal function and to tubular necrosis. Bosentan is effective in protecting kidneys from this cold ischaemia reperfusion damage. Non-selective ET(A)/ET(B) receptor antagonists might be potentially useful in clinical renal transplantation.