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: Rosanna Di Paola, Tiziana Genovese, Daniela Impellizzeri, Akbar Ahmad, Salvatore Cuzzocrea, Emanuela Esposito
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 700 Issue 1-3 Pg. 134-46 (Jan 30 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23291313 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Biomarkers
• Cell Adhesion Molecules
• Interleukin-1beta
• Receptors, Tumor Necrosis Factor, Type I
• Tumor Necrosis Factor-alpha
• 3-nitrotyrosine
• Tyrosine
• Infliximab

Topics

• Acute Kidney Injury (etiology, genetics, metabolism, pathology)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Apoptosis (drug effects)
• Biomarkers (metabolism)
• Cell Adhesion Molecules (metabolism)
• Gene Deletion
• Gene Expression Regulation (drug effects)
• Gene Knockout Techniques
• Inflammation (etiology, genetics, metabolism, pathology)
• Infliximab
• Interleukin-1beta (pharmacology)
• Kidney (drug effects, metabolism, pathology)
• Lipid Peroxidation (drug effects)
• Male
• Mice
• Neutrophil Infiltration (drug effects)
• Oxidative Stress (drug effects)
• Receptors, Tumor Necrosis Factor, Type I (deficiency, genetics)
• Reperfusion Injury (complications)
• Tumor Necrosis Factor-alpha (pharmacology)
• Tyrosine (analogs & derivatives, biosynthesis)