The proteasome inhibitor bortezomib has successful administrated in kidney transplant recipients with acute or chronic antibody-mediated rejection, but there were some unfavorable cases which arised acute tubular necrosis(ATN) in pathological examination of grafts early after surgery. Here, we evaluated the effect of  the proteasome inhibitor bortezomib and of the selective immunoproteasome inhibitor ONX-0914 on acute kidney injury(AKI) after ischemia reperfusion of graft. Mice were subjected to renal IRI by clamping the renal pedicles for 30 min followed by reperfusion for 3, 24, and 48 h. Before surgery, they were pretreated with bortezomib or ONX-0914 or vehicle intravenously 12 h and 2 h before induction of IRI. Serum creatinine, usea nitrogen and tubular necrosis were significantly increased in bortezomib(high and medium density ) compared with vehicle-treated mice, but decreased in ONX-0914 mice. Infiltration of CD4+ T cells and macrophage significantly decreased in bortezomib and ONX-0914-treated mice, and a decreased oxidative stress in the kidneys. On the contrary, the apoptosis of renal tubular epithelial cells was increased in bortezomib-treated mice’ kidneys compared with ONX-0914 and vehicle-treated controls. Increased protein and mRNA expression of proapoptotic factors were detected in kidneys of bortezomib-treated mice. In brief, bortezomib shows a certain cytotoxicity to renal tubular epithelial cell during IRI by leading to incerased apoptosis. The results render immunoproteasome an excellent target for anti-rejection and protecting graft in the field of organ transplantation.

Key Words: proteasome; immunoproteasome; IRI; transplantation