The renal injury and inflammation caused by ischemia-reperfusion are reduced by genetic inhibition of TNF-αR1: A comparison with infliximab treatment

The role of the tumor necrosis factor (TNF)-alpha in the pathophysiology of renal ischemia/reperfusion (I/R) injury is unclear. We investigate the effects of TNF-alpha R1 gene deletion and infliximab administration on the degree of renal injury induced by I/R. TNF-alpha R1 knockout (TNF-alpha R1KO) and wild-type (TNF-alpha WT) mice were subjected to bilateral renal artery occlusion (30 min) and reperfusion (24 h). Infliximab (10 mg/kg subcutaneously, s.c.) was administered 1 h before ischemia. At the end of experiments, urea, creatinine, gamma GT, and AST were measured to assess renal function and reperfusion injury. Markers of oxidative stress, pro-inflammatory mediators, iNOS, COX-2, and NF-kappa B signaling pathway were measured. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels were measured to study polymorphonuclear cell infiltration and lipid peroxidation. TNF-alpha R1 gene deletion and infliximab administration prevented the increase of urea, creatinine, gamma GT, kidney AST levels, iNOS and COX-2 expression, NF-kappa B translocation, MPO activity and MDA levels. TNF-alpha R1 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-alpha plays an important role in I/R injury and put forward the hypothesis that modulation of TNF-alpha expression may represent a novel and possible strategy. (C) 2012 Elsevier B.V. All rights reserved.