Liang Mingyu, Lee Norman H, Wang Hongying, Greene Andrew S, Kwitek Anne E, Kaldunski Mary L, Luu Truong V, Frank Bryan C, Bugenhagen Scott, Jacob Howard J, Cowley Allen W
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Physiol Genomics. 2008 Jun 12;34(1):54-64. doi: 10.1152/physiolgenomics.00031.2008. Epub 2008 Apr 22.
The Dahl salt-sensitive (SS) rat is a widely used model of human salt-sensitive hypertension and renal injury. We studied the molecular networks that underlie the complex disease phenotypes in the SS model, using a design that involved two consomic rat strains that were protected from salt-induced hypertension and one that was not protected. Substitution of Brown Norway (BN) chromosome 13 or 18, but not 20, into the SS genome was found to significantly attenuate salt-induced hypertension and albuminuria. Gene expression profiles were examined in the kidneys of SS and consomic SS-13(BN), SS-18(BN), and SS-20(BN) rats with a total of 240 cDNA microarrays. The substituted chromosome was overrepresented in genes differentially expressed between a consomic strain and SS rats on a 0.4% salt diet. F5, Serpinc1, Slc19a2, and genes represented by three other expressed sequence tags (ESTs), which are located on chromosome 13, were found to be differentially expressed between SS-13(BN) and all other strains examined. Likewise, Acaa2, B4galt6, Colec12, Hsd17b4, and five other ESTs located on chromosome 18 exhibited expression patterns unique to SS-18(BN). On exposure to a 4% salt diet, there were 184 ESTs in the renal cortex and 346 in the renal medulla for which SS-13(BN) and SS-18(BN) shared one expression pattern, while SS and SS-20(BN) shared another, mirroring the phenotypic segregation among the four strains. Molecular networks that might contribute to the development of Dahl salt-sensitive hypertension and albuminuria were constructed with an approach that merged biological knowledge-driven analysis and data-driven Bayesian probabilistic analysis.
达尔盐敏感（SS）大鼠是一种广泛应用于人类盐敏感性高血压和肾损伤研究的模型。我们利用一种设计方法研究了SS模型中复杂疾病表型背后的分子网络，该设计涉及两个对盐诱导高血压具有抗性的近交系大鼠品系和一个不具抗性的品系。研究发现，将挪威棕鼠（BN）的第13或18号染色体（而非第20号染色体）导入SS基因组，可显著减轻盐诱导的高血压和蛋白尿。我们使用总共240个cDNA微阵列检测了SS大鼠以及近交系SS-13(BN)、SS-18(BN)和SS-20(BN)大鼠肾脏中的基因表达谱。在0.4%盐饮食条件下，近交系大鼠和SS大鼠之间差异表达的基因中，导入的染色体出现频率过高。位于第13号染色体上的F5、Serpinc1、Slc19a2以及其他三个表达序列标签（EST）所代表的基因，在SS-13(BN)与所有其他检测品系之间存在差异表达。同样，位于第18号染色体上的Acaa2、B4galt6、Colec12、Hsd17b4以及其他五个EST呈现出SS-18(BN)特有的表达模式。在4%盐饮食条件下，肾皮质中有184个EST，肾髓质中有346个EST，SS-13(BN)和SS-18(BN)共享一种表达模式，而SS和SS-20(BN)共享另一种表达模式，这反映了四个品系之间的表型分离。我们采用一种融合生物知识驱动分析和数据驱动贝叶斯概率分析的方法，构建了可能导致达尔盐敏感性高血压和蛋白尿发生发展的分子网络。
