p38 MAPK mediates renal tubular cell TNF-α production and TNF-α-dependent apoptosis during simulated ischemia

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Abstract
Ischemia causes renal tubular cell loss through apoptosis; however, the mechanisms of this process remain unclear. Using the renal tubular epithelial cell line LLC-PK1, we developed a model of simulated ischemia (SI) to investigate the role of p38 MAPK (mitogen-activated protein kinase) in renal cell tumor necrosis factor-α (TNF-α) mRNA production, protein bioactivity, and apoptosis. Results demonstrate that 60 min of SI induced maximal TNF-α mRNA production and bioactivity. Furthermore, 60 min of ischemia induced renal tubular cell apoptosis at all substrate replacement time points examined, with peak apoptotic cell death occurring after either 24 or 48 h. p38 MAPK inhibition abolished TNF-α mRNA production and TNF-α bioactivity, and both p38 MAPK inhibition and TNF-α neutralization (anti-porcine TNF-α antibody) prevented apoptosis after 60 min of SI. These results constitute the initial demonstration that 1) renal tubular cells produce TNF-α mRNA and biologically active TNF-α and undergo apoptosis in response to SI, and 2) p38 MAPK mediates renal tubular cell TNF-α production and TNF-α-dependent apoptosis after SI.