Genome-wide transcriptome analysis of hypothalamus in rats with inherited stress-induced arterial hypertension

Abstract

Background: The hypothalamus has an important role in the onset and maintenance of hypertension and stress responses. Rats with inherited stress-induced arterial hypertension (ISIAH), reproducing the human stress-sensitive hypertensive state with predominant involvement of the neuroendocrine hypothalamic-pituitary-adrenal and sympathoadrenal axes, were used for analysis of the hypothalamus transcriptome.

Results: RNA-seq analysis revealed 139 genes differentially expressed in the hypothalami of hypertensive ISIAH and normotensive Wistar Albino Glaxo (WAG) rats. According to the annotation in databases, 18 of the differentially expressed genes (DEGs) were associated with arterial hypertension. The Gene Ontology (GO) functional annotation showed that these genes were related to different biological processes that may contribute to the hypertension development in the ISIAH rats. The most significantly affected processes were the following: regulation of hormone levels, immune system process, regulation of response to stimulus, blood circulation, response to stress, response to hormone stimulus, transport, metabolic processes, and endocrine system development. The most significantly affected metabolic pathways were those associated with the function of the immune system and cell adhesion molecules and the metabolism of retinol and arachidonic acid. Of the top 40 DEGs making the greatest contribution to the interstrain differences, there were 3 genes (Ephx2, Cst3 and Ltbp2) associated with hypertension that were considered to be suitable for further studies as potential targets for the stress-sensitive hypertension therapy. Seven DEGs were found to be common between hypothalamic transcriptomes of ISIAH rats and Schlager mice with established neurogenic hypertension.

Conclusions: The results of this study revealed multiple DEGs and possible mechanisms specifying the hypothalamic function in the hypertensive ISIAH rats. These results provide a basis for further investigation of the signalling mechanisms that affect hypothalamic output related to stress-sensitive hypertension development.

Fig. 1

Heatmap of the differentially expressed genes in the hypothalami of the ISIAH and WAG rats. Dendrograms were constructed using hierarchical ‘complete linkage’ clustering by Euclidean distance. Yellow depicts genes that were up-regulated in a sample, and red depicts those that were down-regulated

Fig. 2

The relative mRNA abundance measured by qPCR. The relative mRNA abundance was calculated as the ratio of normalized (mRNA/Rpl30) mRNA level in experimental ISIAH samples to normalized (mRNA/Rpl30) mRNA level in control WAG samples. The normalized mRNA level in control samples of the WAG rats was assigned a value of 1. Vertical bars show the standard error of the mean, and significance of inter-strain difference is indicated by *p < 0.05, **p < 0.01, ***p < 0.001