Combined genealogical, mapping, and expression approaches to identify spontaneously hypertensive rat hypertension candidate genes.

Institute for Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA.
Hypertension (Impact Factor: 7.63). 05/2005; 45(4):698-704. DOI: 10.1161/01.HYP.0000156498.78896.37
Source: PubMed

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 present approach identifies a number of genes that may influence blood pressure in SHR by virtue of allelic effects on gene expression.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Spontaneously hypertensive rats (SHR) have been used frequently as a model for human essential hypertension. However, both the SHR and its normotensive control, the Wistar Kyoto rat (WKY), consist of genetically different sublines. We tested the hypothesis that the pathophysiology of vascular remodeling in hypertension differs among rat sublines.
    PLoS ONE 09/2014; 9(9):e107998. · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pentaerythritol tetranitrate is devoid of nitrate tolerance and shows no reproductive or developmental toxicity in animal studies. Recently, pentaerythritol tetranitrate has been demonstrated to reduce the risk of intrauterine growth restriction and the risk of preterm birth in women with abnormal placental perfusion. This study was conducted to test the perinatal programming effect of pentaerythritol tetranitrate in spontaneously hypertensive rats, a rat model of genetic hypertension. Parental spontaneously hypertensive rats were treated with pentaerythritol tetranitrate (50 mg/kg per day) during pregnancy and lactation periods; the offspring received standard chow without pentaerythritol tetranitrate after weaning. Maternal treatment with pentaerythritol tetranitrate had no effect on blood pressure in male offspring. In the female offspring, however, a persistent reduction in blood pressure was observed at 6 and 8 months. This long-lasting effect was accompanied by an upregulation of endothelial nitric oxide synthase, mitochondrial superoxide dismutase, glutathione peroxidase 1, and heme oxygenase 1 in the aorta of 8-month-old female offspring, which was likely to result from epigenetic changes (enhanced histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation) and transcriptional activation (enhanced binding of DNA-directed RNA polymerase II to the transcription start site of the genes). In organ chamber experiments, the endothelium-dependent, nitric oxide-mediated vasodilation to acetylcholine was enhanced in aorta from female offspring of the pentaerythritol tetranitrate-treated parental spontaneously hypertensive rats. In conclusion, maternal pentaerythritol tetranitrate treatment leads to epigenetic modifications, gene expression changes, an improvement of endothelial function and a persistent blood pressure reduction in the female offspring.
    Hypertension 11/2014; · 7.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epoxyeicosatrienoic acids (EETs) have antihypertensive properties and play a role in maintaining the renal microvascular function. EETs mediate vasodilation of rat preglomerular microvessels and activate ion channels. Ephx2 codes for a soluble epoxide hydrolase (sEH), which catalyzes EET degradation. The renal cortex and medulla were tested for Ephx2 mRNA level in ISIAH rats with hereditary stress-sensitive hypertension and in normotensive WAG rats at rest and in emotional stress. Ephx2 transcriptional activity in ISIAH rats was significantly higher than in WAG rats at rest and in stress by both microarray analysis and realtime PCR. The results implicated Ephx2 in controlling and modulating the vascular tone in the kidney in both hypertensive ISIAH and normotensive WAG rats.
    Molecular Biology 11/2013; 47(6). · 0.74 Impact Factor


1 Download