Oxidants, Mitochondria,and Renal Ischemia/Reperfusion

点击翻译按钮获取中文摘要

This proposal addresses a critical issue in transplantation biology by focusing on the early injury (30 minutes to 2 days) following ischemic damage to the kidney during donor harvesting and/or preservation techniques, prior to transplantation. Mitochondrial dysfunction occurs during ischemia/reperfusion (I/R) episodes, and likely increases intra- mitochondrial reactive oxygen species (ROS) production. This study both extends and compliments the PI's in vitro and in vivo observations that during renal transplantation manganese superoxide dismutase (MnSOD), the major antioxidant in the mitochondria, is tyrosine nitrated and inactivated. The net result of loss of MnSOD activity is damage to sensitive electron transport systems and an accompanying increase in ROS production, thus amplifying further cellular injury. Preliminary studies using an in vivo rat kidney I/R model suggest that MnSOD is tyrosine nitrated early during renal I/R injury. These data are consistent with increased ROS-mediated injury during I/R and suggest that MnSOD is an early target that may result in oxidative injury and predispose the kidney to subsequent injury. We hypothesize that renal preservation and I/R leads to increased oxidative stress via alterations in MnSOD protein, which contributes to renal and mitochondrial injury prior to transplantation. The aims of this proposal are to determine the role that increased oxidant production has on the early events leading to renal dysfunction following preservation and I/R in vivo. Clearly, kidney damage occurs during I/R, therefore, strategies to limit the extent of renal damage during the cold and/or warm ischemic periods would most certainly improve graft function following renal transplantation. An underlying theme of these studies is to relate the increased ROS production to loss of MnSOD function during organ preservation and I/R. This information will be helpful in determining possible therapeutic interventions for improving current techniques in renal preservation and transplantation.