Knoll Kristen E, Pietrusz Jennifer L, Liang Mingyu
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Physiol Genomics. 2005 Apr 14;21(2):222-9. doi: 10.1152/physiolgenomics.00231.2004. Epub 2005 Feb 15.
The understanding of common and tissue-specific molecular alterations in diabetes, particularly at early stages, is limited and fragmental. In the present study, we systematically compared transcriptome responses in four important diabetic target tissues in rats with 2 wk of streptozotocin (STZ)-induced diabetes. At this stage of diabetes, the skeletal muscle exhibited the highest transcriptome sensitivity to the STZ treatment with nearly 17% of the transcriptome being altered (false discovery rate, 1.6%) compared with approximately 3% in the cardiac left ventricle, renal cortex, and retina. Similarity in transcriptome response among tissues was low, with the highest similarity being 2.2% between skeletal muscle and the left ventricle. Several biological processes or cellular components, such as lipid metabolism in the left ventricle and collagen in the renal cortex, were significantly overrepresented in the responsive genes than in the entire array. Particularly interesting cases of common or tissue-specific regulation included decorin and CD36, which were upregulated in several tissues, and serum/glucocorticoid-regulated kinase and four and a half LIM domains 2, which were upregulated only in the renal cortex. Further biochemical analyses indicated that the thiol and oxidative stress pathway was altered in a tissue-specific manner at several levels including transcript abundance, content of reduced thiols, and lipid peroxidation, providing an example of the potential biological relevance of tissue-specific transcript regulation. These results provided a transcriptome-wide view of the molecular alterations across several key tissues in early diabetes. It appears that both common pathways and, perhaps more importantly, tissue-specific mechanisms are involved in the adaptation to diabetes or the initiation of diabetic complications.
对糖尿病中常见的和组织特异性分子改变的理解，尤其是在早期阶段，是有限且零散的。在本研究中，我们系统地比较了链脲佐菌素（STZ）诱导糖尿病2周的大鼠的四个重要糖尿病靶组织中的转录组反应。在糖尿病的这个阶段，骨骼肌对STZ治疗表现出最高的转录组敏感性，近17%的转录组发生改变（错误发现率为1.6%），相比之下，左心室、肾皮质和视网膜中约为3%。组织间转录组反应的相似性较低，骨骼肌和左心室之间的最高相似性为2.2%。一些生物学过程或细胞成分，如左心室中的脂质代谢和肾皮质中的胶原蛋白，在反应性基因中比在整个阵列中显著富集。常见或组织特异性调控的特别有趣的例子包括核心蛋白聚糖和CD36，它们在几个组织中上调，以及血清/糖皮质激素调节激酶和四个半LIM结构域2，它们仅在肾皮质中上调。进一步的生化分析表明，硫醇和氧化应激途径在几个水平上以组织特异性方式改变，包括转录本丰度、还原型硫醇含量和脂质过氧化，这为组织特异性转录调控的潜在生物学相关性提供了一个例子。这些结果提供了早期糖尿病中几个关键组织分子改变的全转录组视图。似乎共同途径以及可能更重要的是组织特异性机制都参与了对糖尿病的适应或糖尿病并发症的发生。
