Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion

The purpose of this study was to determine whether isolated renal ischemia and reperfusion (yR) induces renal tumor necrosis factor (TNF) mRNA product ion, TNF protein expression, or TNF bioactivity and, if so, whether local/e arly TNF production acts as mediator of ischemia-induced, neutrophil-mediat ed renal injury. After rats were anesthetized, varying periods of renal isc hemia, with or without reperfusion, were induced. Kidney mRNA content (RT-P CR), TNF protein expression (ELISA), TNF bioactivity (WEHI-164 cell clone c ytotoxicity assay), and neutrophil infiltration [myeloperoxidase (MPO) assa y] were determined. In other animals, renal MPO and serum creatinine were a ssessed after TNF was neutralized [binding protein (TNF-BP)]. Thirty minute s of ischemia induced renal TNF mRNA. TNF protein expression and bioactivit y peaked after 1 h ischemia and 2 h reperfusion, whereas neutrophil infiltr ation peaked at 4 h reperfusion. TNF-BP neutralized TNF bioactivity, reduce d neutrophil infiltration, and protected postischemic function. These resul ts constitute the initial demonstration that 1) early renal tissue TNF expr ession contributes to neutrophil infiltration and injury after yR and 2) TN F-BP may offer a new adjunctive therapy in renal preservation prior to plan ned ischemic insults.