title: Modulation of chemokine expression during ischemia/reperfusion in transgenic mice overproducing human glutathione peroxidases.
abstract: 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 peroxidases (GP) are protected against kidney I/R injury. Importantly, significant reduction in neutrophil migration was observed in GP mice compared with nontransgenic mice. Analysis of signaling molecules mediating neutrophil activation and recruitment indicates reduction in the level of KC and macrophage inflammatory protein-2 chemokine expression in transgenic animals. The molecular mechanism mediating this effect appears to involve repression of NF-kappaB activation at the level of IkappaBalpha and IkappaBbeta degradation. In the case of IkappaBalpha, no apparent phosphorylation was detected. These results suggest that IkappaBalpha proteolysis is triggered during the renal I/R pro-oxidant state by a still unknown mechanism, which might be different from other stimuli. A central role of NF-kappaB in CXC chemokine activation was demonstrated in cell culture anoxia/ATP repletion experiments as a model of I/R. The data presented indicate the important role of GP-sensitive signal transduction pathways in the development of inflammatory response and tissue injury during I/R.
authors.affiliation: Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway 08854, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ishibashi
authors.forename: M
authors.initials: M
authors.lastname: Weisbrot-Lefkowitz
authors.forename: K
authors.initials: K
authors.lastname: Reuhl
authors.forename: M
authors.initials: M
authors.lastname: Inouye
authors.forename: O
authors.initials: O
authors.lastname: Mirochnitchenko
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015687:Cell Hypoxia; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D007113:Immunity, Innate; D007668:Kidney / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D010766:Phosphorylation; D011485:Protein Binding; D015427:Reperfusion Injury / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D018925:Chemokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D000255:Adenosine Triphosphate; D005979:Glutathione Peroxidase