title: The renal injury and inflammation caused by ischemia-reperfusion are reduced by genetic inhibition of TNF-αR1: a comparison with infliximab treatment.
abstract: The role of the tumor necrosis factor (TNF)-α in the pathophysiology of renal ischemia/reperfusion (I/R) injury is unclear. We investigate the effects of TNF-αR1 gene deletion and infliximab administration on the degree of renal injury induced by I/R. TNF-αR1 knockout (TNF-αR1KO) and wild-type (TNF-αWT) mice were subjected to bilateral renal artery occlusion (30min) and reperfusion (24h). Infliximab (10mg/kg subcutaneously, s.c.) was administered 1h before ischemia. At the end of experiments, urea, creatinine, γGT, and AST were measured to assess renal function and reperfusion injury. Markers of oxidative stress, pro-inflammatory mediators, iNOS, COX-2, and NF-κB signaling pathway were measured. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels were measured to study polymorphonuclear cell infiltration and lipid peroxidation. TNF-αR1 gene deletion and infliximab administration prevented the increase of urea, creatinine, γGT, kidney AST levels, iNOS and COX-2 expression, NF-κB translocation, MPO activity and MDA levels. TNF-αR1 gene deletion and infliximab administration lowered the histological evidence of renal damage associated with I/R and caused a reduction of nitrotyrosine suggesting reduced nitrosative stress. Our results demonstrate that TNF-α plays an important role in I/R injury and put forward the hypothesis that modulation of TNF-α expression may represent a novel and possible strategy.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario Via C. Valeria, Gazzi, 98100 Messina, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzeri
authors.forename: Akbar
authors.initials: A
authors.lastname: Ahmad
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000069285:Infliximab; D053583:Interleukin-1beta / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency* / Q000235:genetics*; D015427:Reperfusion Injury / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D053583:Interleukin-1beta; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D000069285:Infliximab