The functions of the hypothalamic adrenal cortical and sympathetic adrenal medullary systems were studied in rats with inherited stress-induced arterial hypertension (ISIAH strain). A characteristic feature of the ISIAH strain is an increase in arterial blood pressure measured both under basal conditions and after restraint stress in particular. In the control ISIAH rats, the basal plasma ACTH concentration was slightly lower than that in the normotensive Wistar albino Glaxo (WAG) rats, and no differences were found in plasma corticosterone. However, the 0.5-h restraint stress produced higher activation of the adrenal cortex in the ISIAH rats. Gluco- and mineralocorticoid responses to the blood volume reduction stresses and ACTH and corticosterone responses to social stress were stronger in the ISIAH than in the control WAG rats. An increase in epinephrine content in adrenals in the basal state and enhanced response of the sympathetic adrenal medullary system to handling stress were observed in the ISIAH rats. Restraint stress produced significantly higher expression of genes encoding corticotropin-releasing hormone-mRNA in hypothalamus and proopiomelanocortin-mRNA in pituitary in the ISIAH than in the WAG rats. Restraint stress produced a decrease in glucocorticoid receptor (GR) gene expression (GR-mRNA) in hippocampus in the ISIAH, but not in the WAG rats. A persistent increase in tyrosine hydroxylase-mRNA in adrenals of the ISIAH rats was found. It is concluded that the ISIAH rat strain is an appropriate model of stress-sensitive hypertension with the predominant involvement of the hypothalamic adrenal cortical and sympathetic adrenal medullary systems in its pathogenesis.

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. 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. 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.

Fat mass and obesity-associated (FTO) gene has been under close investigation since the discovery of its high impact on the obesity status in 2007 by a range of publications. Recent report on its implication in adipocytes underscored its molecular and functional mechanics in pathology. Still, the population specific features of the locus structure have not been approached in detail. We analyzed the population specific haplotype profiles of FTO genomic locus identified by Genome Wide Association Studies (GWAS) for the high obesity risk by examining eighteen 1000G populations from 4 continental groups. The GWAS SNPs cluster is located in the FTO gene intron 1 spanning around 70 kb. We reconstructed the ancestral state of the locus, which comprised low-risk major allele found in all populations, and two minor risk-associated alleles, each one specific for African and European populations, correspondingly. The locus structure and its allele frequency distribution underscore the high risk allele frequency specifically for the European population. South Asian populations have the second highest frequency of risk alleles, while East Asian populations have the lowest. African population-specific minor allele was only partially risk-associated. All of the GWAS SNPs considered are manifested by low risk alleles as reference (major) ones (p > 0.5) in each of the continental groups. Strikingly, rs1421085, recently reported as a causal SNP, was found to be monomorphic in ancestral (African) populations, implying possible selection sweep in the course of its rapid fixation, as reported previously. The observations underscore varying FTO -linked risk in the manifestation of population specific epidemiology of genetically bound obesity. The results imply that the FTO locus is one of the major genetic determinants for obesity risk from GWAS SNPs set.

The adrenals are known as an important link in pathogenesis of arterial hypertensive disease. The study was directed to the adrenal transcriptome analysis in ISIAH rats with stress-sensitive arterial hypertension and predominant involvement in pathogenesis of the hypothalamic-pituitary-adrenal and sympathoadrenal systems. The RNA-Seq approach was used to perform the comparative adrenal transcriptome profiling in hypertensive ISIAH and normotensive WAG rats. Multiple differentially expressed genes (DEGs) related to different biological processes and metabolic pathways were detected. The discussion of the results helped to prioritize the several DEGs as the promising candidates for further studies of the genetic background underlying the stress-sensitive hypertension development in the ISIAH rats. Two of these were transcription factor genes (Nr4a3 and Ppard), which may be related to the predominant activation of the sympathetic-adrenal medullary axis in ISIAH rats. The other genes are known as associated with hypertension and were defined in the current study as DEGs making the most significant contribution to the inter-strain differences. Four of them (Avpr1a, Hsd11b2, Agt, Ephx2) may provoke the hypertension development, and Mpo may contribute to insulin resistance and inflammation in the ISIAH rats. The study strongly highlighted the complex nature of the pathogenesis of stress-sensitive hypertension. The data obtained may be useful for identifying the common molecular determinants in different animal models of arterial hypertension, which may be potentially used as therapeutic targets for pharmacological intervention.

The renal function plays a leading role in long-term control of arterial pressure. The comparative analysis of renal cortex transcriptome in ISIAH rats with inherited stress-induced arterial hypertension and normotensive WAG rats was performed using RNA-Seq approach. The goal of the study was to identify the differentially expressed genes (DEGs) related to hypertension and to detect the pathways contributing to the differences in renal functions in ISIAH and WAG rats. The analysis revealed 716 genes differentially expressed in renal cortex of ISIAH and WAG rats, 42 of them were associated with arterial hypertension and regulation of blood pressure (BP). Several Gene Ontology (GO) terms significantly enriched with DEGs suggested the existence of the hormone dependent interstrain differences in renal cortex function. Multiple DEGs were associated with regulation of blood pressure and blood circulation, with the response to stress (including oxidative stress, hypoxia, and fluid shear stress) and its regulation. Several other processes which may contribute to hypertension development in ISIAH rats were: ion transport, regulation of calcium ion transport, homeostatic process, tissue remodeling, immune system process and regulation of immune response. KEGG analysis marked out several pathways significantly enriched with DEGs related to immune system function, to steroid hormone biosynthesis, tryptophan, glutathione, nitrogen, and drug metabolism. The results of the study provide a basis for identification of potential biomarkers of stress-sensitive hypertension and for further investigation of the mechanisms that affect renal cortex function and hypertension development.