Induction of heme oxygenase-1 in kidneys during ex vivo warm perfusion

Background. Reperfusion injury plays a pivotal role in the occurrence of delayed graft function and chronic rejection. Heme oxygenase-1 (HO-1), an inducible heat shock protein, is known to have cytoprotective effects against reperfusion injury. We report on the potential for ex vivo induction of HO-1 expression during acellular warm perfusion of canine kidneys, using cobalt protoporphyrin (CoPP) as an HO-1 inducer and zinc protoporphyrin as an HO-1 inhibitor. Methods. Canine kidneys were used to evaluate HO-1 increase after exposure to warm ischemia (WI), hypothermic perfusion (mechanical perfusion [MP], 4degreesC), warm perfusion (exsanguineous metabolic support [EMS], 32degreesC), or various combinations. Results. WI alone, MP, or EMS with or without WI, had no effect on HO-1 activity. However, the presence of CoPP during EMS perfusion resulted in a significant increase in kidney HO-1 activity, whereas zinc protoporphyrin reduced HO-1 activity. The presence of CoPP during MP did not induce elevated HO-1 expression. The results of our study demonstrate that sufficient metabolism supporting new protein synthesis resulting in the expression of the protective gene, HO-1, can be accomplished during an acellular normothermic perfusion using CoPP. Most importantly, the time required for ex vivo HO-1 induction with this method is compatible with the current time frame for which organs are preserved clinically. Conclusions. The ability to induce HO-1 expression ex vivo eliminates the need for donor therapy to induce HO-1 increase before retrieving organs and also prevents the potential of decreasing HO-1 enzyme activity that is known to occur with temperature-mediated inhibition of oxidative metabolism during hypothermic organ storage.