Regulation of JNK/ERK activation, cell apoptosis, and tissue regeneration by monoamine oxidases after renal ischemia-reperfusion.

Reactive oxygen species (ROS) contribute to the ischemia-reperfusion injury. In kidney, the intracellular sources of ROS during ischemia-reperfusion are still unclear. In the present study, we investigated the role of the catecholamine-degrading enzyme monoamine oxidases (MAOs) in hydrogen peroxide (H2O2) generation after reperfusion and their involvement in cell events leading to tissue injury and recovery. In a rat model of renal ischemia-reperfusion, we show concomitant MAO-dependent H2O2 production and lipid peroxidation in the early reperfusion period. Rat pretreatment with the irreversible MAO inhibitor pargyline resulted in the following: i) prevented H2O2 production and lipid peroxidation; ii) decreased tubular cell apoptosis and necrosis, measured by TUNEL staining and histomorphological criteria; and iii) increased tubular cell proliferation as determined by proliferating cell nuclear antigen expression. MAO inhibition also prevented Jun N-terminal kinase phosphorylation and promoted extracellular signal-regulated kinase activation, two mitogen-activated protein kinases described as a part of a "death" and "survival" pathway after ischemia-reperfusion. This work demonstrates the crucial role of MAOs in mediating the production of injurious ROS, which contribute to acute apoptotic and necrotic cell death induced by renal ischemia-reperfusion in vivo. Targeted inhibition of these oxidases could provide a new avenue for therapy to prevent renal damage and promote renal recovery after ischemia-reperfusion.