Comparative gene expression analysis in the liver, kidney and blood vessels during renal injury after repeated exposure to tacrolimus in Sprague-Dawley rats

To elucidate the molecular mechanisms associated with renal injury based on multi-organ interactions, we simultaneously examined the changes in expression profiles of the liver, kidneys, and blood vessels after treatment with the nephrotoxic drug tacrolimus. Sprague-Dawley rats were treated daily with tacrolimus and sacrificed 28 d after oral administration. Serum biochemistry analysis of the major injury markers was performed. Histopathological characteristics were also observed. Total RNA was extracted from the liver, kidneys, and blood vessels from the thoracic aorta, followed by microarray analysis. Differentially expressed genes were selected based on 1.5-fold changes and statistical significance (P<0.05). The effects of three dosages of tacrolimus on transcription levels were analyzed within and among the three organs. Gene functions, as well as the biological and toxicological functions of the differentially regulated genes, were analyzed using Ingenuity Pathways Analysis (IPA). IPA identified genes involved in metabolic activation, including lipid metabolism, renal tubule injury, and cell proliferation in tacrolimus-treated livers, kidneys, and blood vessels, respectively. In response to tacrolimus treatment, genes related to lipid metabolic responses were regulated in the three organs similarly. Genes associated with inflammatory response were regulated in the liver and kidneys similarly. Based on the results from this study, we suggest the molecular pathways involved in the response to tacrolimus in multiple organs. We also provide information about candidate genes, to evaluate the toxicity induced by tacrolimus. These results might be helpful to elucidate the underlying mechanisms of nephrotoxicity by interaction among multiple organs.