| Summary: | 碩士 === 臺北醫學大學 === 生物醫學技術研究所 === 92 === Celecoxib is a cyclooxygenases-2 (COX-2) selective nonsteroidal anti-inflammatory drug (NSAIDs). A serious side effect of COX inhibitors is renal damage. To investigate the molecular basis of the renal injury, I evaluated the expression of the stress marker, heme oxygenase-1 (HO-1), in celecoxib-stimulated mesangial cells. Celecoxib induced dose- and time-dependent increases of HO-1 expression in glomerular mesangial cells. Pretreatmnet of mesangial cells with l-N-acetylcysteine, a free radical scavenger, suppressed celecoxib-induced HO-1 expression, suggesting reactive oxygen species (ROS) may play a role in this process. Indeed, incubation of glomerular mesangial cells with celecoxib increased ROS generation. Celecoxib-stimulated JNK kinase activity is inhibited by treatment with SP600125 (a specific JNK inhibitor). Consistently, celecoxib-induced HO-1 expression was attenuated by SP 600125, but not PD 98059 (a specific p42/44 MAPK inhibitor) or SB203580 (a specific p38 MAPK inhibitor). On the other hand, LY 294002, a phosphatidylinositol 3-kinase (PI3K)-specific inhibitor, inhibited celecoxib-induced HO-1 expression in cultured mesangial cells as demonstrated by inhibition of the phosphorylation of the PDK-1 and Akt/protein kinase B (PKB). In conclusion, these data suggest that celecoxib increases free radical generation, which triggers a signal transduction cascade involving JNK and PI3K signaling pathways, which in turn induces HO-1 expression in glomerular mesangial cells.
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