Kidney ischemia and reperfusion injury (IRI) is associated with a high mortality rate, which is attributed to tubular oxidative stress and necrosis; however, an effective approach to limit IRI remains elusive. Spermidine, a naturally occurring polyamine, protects yeast cells against aging through the inhibition of oxidative stress and necrosis. In the present study, spermidine supplementation markedly attenuated increases in plasma creatinine concentration and tubular injury score after IRI. In addition, exogenous spermidine potently inhibited oxidative stress, especially lipid peroxidation after IRI in kidneys and exposure to hydrogen peroxide in kidney proximal tubular cells, suppressing plasma membrane disruption and necrosis. Consistent with spermidine supplementation, upregulation of ornithine decarboxylase (ODC) in human kidney proximal tubular cells significantly diminished lipid peroxidation and necrosis induced by hydrogen peroxide-induced injury. Conversely, ODC deficiency significantly enhanced lipid peroxidation and necrosis after exposure to hydrogen peroxide. Finally, small interfering RNA-mediated ODC inhibition induced functional and histological damage in kidneys as well as it increased lipid hydroperoxide levels after IRI. In conclusion, these data suggest that spermidine level determines kidney proximal tubular damage through oxidative stress and necrosis induced by IRI, and this finding provides a novel target for prevention of tubular damage induced by IRI.
Keywords: Ischemia and reperfusion injury; Lipid peroxidation; Necrosis; Ornithine decarboxylase; Spermidine.