Apoptosis and chemokine induction after renal ischemia-reperfusion

Background. One of the earliest prerequisites for the development of inflam mation after ischemia-reperfusion (UR) is local chemokine expression. We re cently demonstrated that apoptosis, characterized by intracellular caspase- activation, contributes to the development of inflammation after I/R. Methods. The contribution of apoptosis was investigated using the pan-caspa se inhibitor Z-Val-AZa-Asp(OMe)-CH2F in a murine model of renal I/R. Renal expression of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC was studied using RT-PCR and immunohistology. Measuring myeloperoxidase activity and serum ureum and creatinine levels assessed neutrophil influx a nd kidney dysfunction. Results. We demonstrate renal up-regulation of KC and MIP-2 after 1 to 16 h r of reperfusion. Treatment with the caspase inhibitor Z-Val-Ala-Asp(OMe)-C H2F effectively prevented I/R-induced renal apoptosis, KC, and MIP-2 up-reg ulation after 2 hr of reperfusion as well as neutrophil influx and function al impairment after 24 hr of reperfusion. Conclusions. These data for the first time show that chemokine induction fo llowing I/R is dependent on caspase activation.