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1 Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Dept. Pharmacology and Physiology, George Washington University Medical Center, Washington, District of Columbia, United States
3 Department of Functional Genomics, The Institute of Genome Research, Rockville, Maryland, United States
4 Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
5 Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
6 Human Molecular and Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: mliang{at}mcw.edu.
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-13BN, SS-18BN, and SS-20BN rats using a total of 240 cDNA microarrays. The substituted chromosome was over-represented in genes differentially expressed between a consomic strain and SS 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-13BN and all other strains examined. Likewise, Acaa2, B4galt6, Colec12, Hsd17b4, and five other ESTs located on chromosome 18 exhibited expression patterns unique to SS-18BN. Upon exposure to a 4% salt diet, there were 184 ESTs in the renal cortex and 346 in the renal medulla for which SS-13BN and SS-18BN shared one expression pattern, while SS and SS-20BN 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 using an approach that merged biological knowledge-driven analysis and data-driven Bayesian probabilistic analysis.
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