Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes

Abstract

Abstract-Allelic expression in genes has become recognized as a heritable trait by which phenotypes are generated. We have examined gene expression in the rat kidney using genome-wide microarray technology (Affymetrix). Gene expression was determined across 4 rat strains, 3 hypertensive spontaneously hypertensive rat (SHR) substrains (SHR-A3, SHR-B2, and SHR-C), and a normotensive strain (Wistar-Kyoto [WKY]). Expression measurements were made in multiple animals from all strains at 4 time points (4 weeks, 8 weeks, 12 weeks, and 18 weeks of age), covering the prehypertensive period in SHR (4 weeks), and the period of rapidly rising blood pressure (8 and 12 weeks) and of sustained hypertension (18 weeks). Regression analysis revealed a close relationship across all strains during the first 3 time points, after which SHR-A3 became a substantial outlier. SHR-B2 and SHR-C demonstrated a very close relationship in gene expression at all times but also showed increased differences compared with the other strains at 18 weeks of age. We identified genes that were consistently different in expression, comparing all SHR substrains at each time point with WKY. The resulting list of genes was compared with blood pressure quantitative trait loci reported for SHR to refine a number of genes consistently differentially expressed between SHR substrains and WKY, persistently differentially expressed across multiple time points, and located in SHR blood pressure-determinative regions of the genome. Genealogical relationships and SHR substrain intercrosses suggest that genes responsible for heritable hypertension in SHR are shared across SHR substrains.

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

“…[17][18][19] Figure 2 summarizes the results collected from these studies. As indicated, the substrains of WKY and SHR had two haplotypes of the Ephx2 gene, which lead to high and low sEH expression levels.…”

“…50 A similar bioinformatics strategy may be able to dissect the network underlying hypertension in SHR/SHRSP. 19,51 In addition to such bioinformatics studies, another tool may be useful to promote physiological, cell biological and biochemical studies: a 'reconstructed' SHR with a few genomic fragments of SHR/SHRSP on the WKY background.…”

1H NMR-based metabonomic analysis of urine from young spontaneously hypertensive rats

“…motensive rats, i.e., Wistar Kyoto rats (WKY) are of great interest because they are expected to provide insights into blood pressure regulation in human essential hypertension [4].…”

Relation of Blood Pressure Quantitative Trait Locus on Rat Chromosome 1 to Hyperactivity of Rostralventrolateral Medulla

“…These genes include Arix, a transcription factor regulating the development of the sympathetic nervous system, as well as the expression of dopamine ␤-hydroxylase 24 -26 ; Ntrk3, a receptor for neurotropin 3 27 ; Arrb1, a cofactor regulating the internalization of the ␤-adrenergic receptors and angiotensin receptors 28 ; Nox4, a subunit of NADPH oxidase 29 ; and Homer 2, a regulator of the metabolic glutamate receptors. 30,31 In future studies, it will be necessary to reduce the number of candidate genes using both their positional and functional information to identify the responsible gene(s) and to confirm the roles of increased RVLM activity in the pathogenesis of hypertension.…”