Modulation of chemokine expression during ischemia/reperfusion in transgenic mice overproducing human glutathione peroxidases

Renal ischemia/reperfusion (I/R) injury is a major cause of kidney damage, There is accumulating evidence that inflammatory reactions are involved in the pathogenesis of this process, Our studies demonstrate that transgenic: mice overexpressing human extracellular and intracellular glutathione perox idases (GP) are protected against kidney I/R injury, Importantly, significa nt reduction in neutrophil migration,vas observed in GP mice compared with nontransgenic mice. Analysis of signaling molecules mediating neutrophil ac tivation and recruitment indicates reduction in the level of KC and macroph age inflammatory protein-2 chemokine expression in transgenic animals. The molecular mechanism mediating this effect appears to involve repression of NF-kappa B activation at the level of I kappa B alpha and I kappa B beta de gradation. In the case of I kappa B alpha, no apparent phosphorylation was detected. These results suggest that I kappa B alpha proteolysis is trigger ed during the rend I/R pro-oxidant state by a still unknown mechanism, whic h might be different from other stimuli. A central role of NF-kappa B in CS C chemokine activation nas demonstrated in cell culture anoxia/ATP repletio n experiments as a model of I/R, The data presented indicate the important role of GP-sensitive signal transduction pathways in the development of inf lammatory response and tissue injury during I/R.