S2: WHOLE GENOME EXPRESSION PROFILING OF MINIPIG LIVER AND KIDNEY
WHOLE GENOME EXPRESSION PROFILING OF MINIPIG LIVER AND KIDNEY IN RESPONSE TO DICLOFENAC
Hannover Medical School, Hannover, Germany
PhD Research Assistant
Abstract: Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) commonly used for the treatment of arthritis and chronic pain associated with musculoskeletal injuries. However, its use is associated with a variety of adverse drug reaction, including rare but severe hepato- and nephrotoxicity. The molecular mechanism leading to diclofenac induced hepato- and renal damage remains uncertain. For a better understanding of mechanism of diclofenac mediated organ toxicity, whole genome transcriptional responses were investigated in the liver and kidney of the minipig. Bioinformatics defined (a) functional enrichment and GO mapping (b) co-occupancy of TFBS at promoters of regulated genes (c) enabled construction of regulatory gene/protein-interaction networks and (d) defined key master molecules and their associated networks. The integrated clinical pathology, molecular biology and computational biology approaches revealed immune mediated injury as a major cause of toxicity. The constructed gene networks were enriched by over represented transcription factors and their co-occupancy at gene specific promoters described the transcriptional regulation of DEGs involved in immune and stress responses. The proposed key master regulators and their corresponding molecular circuits can alter pro- and anti-inflammatory signalling cascades leading to organ toxicity. This study might be helpful to stimulate research on the mechanism(s) of hepato- and renal toxicity of diclofenac.