Published online before print March 1, 2007, doi: 10.1161/01.RES.0000261961.41889.9c
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Submitted on July 25, 2006
Revised on February 16, 2007
Accepted on February 20, 2007
Genetic Dissection of a Blood Pressure Quantitative Trait Locus on Rat Chromosome 1 and Gene Expression Analysis Identifies SPON1 as a Novel Candidate Hypertension Gene
Jenny-Rebecca Clemitson ;
From the Department of Cardiovascular Sciences (J.-R.C., R.J.D., S.H., A.J.B., B.R.P., L.H., F.J.C., N.J.S.), University of Leicester, Glenfield Hospital, United Kingdom; Departement de Physiologie et Pharmacologie Clinique (M.L., J.S.), Faculte de Pharmacie, Lyon, France.
* To whom correspondence should be addressed. E-mail: njs{at}le.ac.uk.
A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene, Spon1 that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the Spon1 gene product in SHR kidneys. Spon1 belongs to a family of genes with antiangiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans.
Key words: hypertension • genetics • rats • gene expression • quantitative trait locus
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