Spaceflight-induced gene expression changes in the mouse liver and kidney
To examine the effect of spaceflight on the kidney and liver tissues, NASA carried out a study involving C57BL/6J mice flown on STS-108 for 12 days. We report the first analysis of gene expression in these tissues. Our results indicate tissue-specific changes with 73 and 198 differentially expressed genes in kidney and liver, respectively, and 42 non-tissue specific. Changes suggesting negative regulation of inflammatory processes include increases in anti-inflammatory Zfp36 in the kidney, and decrease in pro-inflammatory molecules in liver: toll-interleukin 1 receptor (TIR) domain containing adaptor protein (Tirap), and Il1α. In addition, six immune response genes showed negative regulation in liver, including chemokine (C-X-C motif) ligand 12, interferon regulatory factor 11, Tirap, CD8 antigen, Igl-VI, Illaα. We observe 3-fold increase in lipocalin 2, which is important in response to infection. These results indicate that elements of the immune system regulatory network are sensitive to spaceflight. Changes in drug-metabolizing enzymes reveal small but significant changes. These appear to be tissue-specific, with most of the altered expression located in the liver. We see up-regulation of the cytochrome P450-dependent monooxygenase system, including Cyp4a, Cyp4b, and Cyp17a, as well as the necessary coenzyme NADPH cytochrome reductase. Alcohol dehydrogenase was significantly down-regulated in liver. This is the most important enzyme involved in the processing of exogenous alcohols. Several phase II members also exhibited altered gene expression, including glutathione s-transferase. a sulfotransferase, and enzymes involved in acylation. These changes do not appear to be sufficiently large to indicate global perturbations in xenobiotic metabolism in response to short-term spaceflight. Non-tissue specific changes were also observed: Cdkn1a (P21), Gadd45, C/EPB, Pdrgl, and Zbtbl6. Both P21 and Gadd45 are essential to growth arrest, and regular tion of the cell cycle. A moderate increase in Txnip may indicate oxidative stress response. Alteration of expression levels for these genes suggests that cellular damage and repair/stress response genes are not tissue-specific. In addition, up to 8-fold increases in metallothionein Mt1/Mt2 occurred in both tissues. Metallothioneins are involved in nitric oxide signaling events, response to heavy metals, and immune response. The results demonstrate that spaceflight-factors cause alteration of gene expression in liver and kidney. Some of these changes are tissue specific, but it is unclear whether the specificity is due to microgravity, fluid shift, dehydration, or other causes. The results indicate that the mouse provides a useful platform for measuring the spaceflight-induced physiological changes that are of concern in space medicine.
