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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
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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 fo...
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Citations
... ISIAH rats are a model of a stress-sensitive form of hypertension with genetically pre-determined activation of the HPA and sympathoadrenal systems [23]. The comparative analysis of hypothalamic transcriptomes of hypertensive ISIAH and control normotensive WAG rats allowed us to identify genes related to the inter-strain differences, many of which are associated with both hypertension and peculiarities of central nervous system functioning [24]. ...
Emotional stress is one of the health risk factors in the modern human lifestyle. Stress exposure can provoke the manifestation of various pathological conditions, one of which is a sharp increase in the blood pressure level. In the present study, we analyzed changes in the transcriptome profiles of the hypothalamus of hypertensive ISIAH and normotensive WAG rats exposed to a single short-term restraint stress (the rat was placed in a tight wire-mesh cage for 2 h). This type of stress can be considered emotional stress. The functional annotation of differentially expressed genes allowed us to identify the most significantly altered biological processes in the hypothalamus of hypertensive and normotensive rats. The study made it possible to identify a group of genes that describe a general response to stress, independent of the rat genotype, as well as a hypothalamic response to stress specific to each strain. The alternatively changing expression of the Npas4 (neuronal PAS domain protein 4) gene, which is downregulated in the hypothalamus of the control WAG rats and induced in the hypothalamus of hypertensive ISIAH rats, is suggested to be the key event for understanding inter-strain differences in the hypothalamic response to stress. The stress-dependent ISIAH strain-specific induction of Fos and Jun gene transcription may play a crucial role in neuronal activation in this rat strain. The data obtained can be potentially useful in the selection of molecular targets for the development of pharmacological approaches to the correction of stress-induced pathologies related to neuronal excitability, taking into account the hypertensive status of the patients.
... To contribute to the effort, several rat strains simulating hu man diseases have been developed in the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences. Thus, the ISIAH rats are characterized by an increased arterial blood pressure and used for studying the causes and treatments of hypertension in humans (Markel, 1992;Markel et al., 1999;Fedoseeva et al., 2016aFedoseeva et al., , 2019Klimov et al., 2016;Ryazanova et al., 2016), the OXYS rats represent a unique selectionbased model of premature ageing and associated diseases (Kozhevnikova et al., 2013;Kolosova et al., 2014;Perepechaeva et al., 2014;Stefanova et al., 2018Stefanova et al., , 2019Stefanova, Kolosova, 2023), rats with pendulum-like movements (the PM strain) with stereotypies and audiogenic epilepsy, and rats with genetic catatonia (the GC rats), a syn drome observed in patients with mental disorders, including schizophrenia (Barykina et al., 1983;Kolpakov et al., 2004;Ryazanova et al., 2017Ryazanova et al., , 2023. ...
The animal models used in biomedical research cover virtually every human disease. RatDEGdb, a knowledge base of the differentially expressed genes (DEGs) of the rat as a model object in biomedical research is a collection of published data on gene expression in rat strains simulating arterial hypertension, age-related diseases, psychopathological conditions and other human afflictions. The current release contains information on 25,101 DEGs representing 14,320 unique rat genes that change transcription levels in 21 tissues of 10 genetic rat strains used as models of 11 human diseases based on 45 original scientific papers. RatDEGdb is novel in that, unlike any other biomedical database, it offers the manually curated annotations of DEGs in model rats with the use of independent clinical data on equal changes in the expression of homologous genes revealed in people with pathologies. The rat DEGs put in RatDEGdb were annotated with equal changes in the expression of their human homologs in affected people. In its current release, RatDEGdb contains 94,873 such annotations for 321 human genes in 836 diseases based on 959 original scientific papers found in the current PubMed. RatDEGdb may be interesting first of all to human geneticists, molecular biologists, clinical physicians, genetic advisors as well as experts in biopharmaceutics, bioinformatics and personalized genomics. RatDEGdb is publicly available at https://www.sysbio.ru/RatDEGdb.
... Because the ISIAH rat strain has been created by selection for a sharp increase in BP under short-term restraint (emotional) stress, we can theorize that genetic features of ISIAH rats may contribute to a decline in stress reactivity during the progression of the disorder in question. This supposition is supported by a report that many genes whose transcription differs between ISIAH and normotensive control rats are associated with the stress response [32][33][34][35][36]. This observation suggests that ISIAH rats-even at rest-are in a state of chronic functional stress. ...
Hypertension is one of the most significant risk factors for many cardiovascular diseases. At different stages of hypertension development, various pathophysiological processes can play a key role in the manifestation of the hypertensive phenotype and of comorbid conditions. Accordingly, it is thought that when diagnosing and choosing a strategy for treating hypertension, it is necessary to take into account age, the stage of disorder development, comorbidities, and effects of emotional-psychosocial factors. Nonetheless, such an approach to choosing a treatment strategy is hampered by incomplete knowledge about details of age-related associations between the numerous features that may contribute to the manifestation of the hypertensive phenotype. Here, we used two groups of male F 2 (ISIAHxWAG) hybrids of different ages, obtained by crossing hypertensive ISIAH rats (simulating stress-sensitive arterial hypertension) and normotensive WAG rats. By principal component analysis, the relationships among 21 morphological, physiological, and behavioral traits were examined. It was shown that the development of stress-sensitive hypertension in ISIAH rats is accompanied not only by an age-dependent (FDR < 5%) persistent increase in basal blood pressure but also by a decrease in the response to stress and by an increase in anxiety. The plasma corticosterone concentration at rest and its increase during short-term restraint stress in a group of young rats did not have a straightforward relationship with the other analyzed traits. Nonetheless, in older animals, such associations were found. Thus, the study revealed age-dependent relationships between the key features that determine hypertension manifestation in ISIAH rats. Our results may be useful for designing therapeutic strategies against stress-sensitive hypertension, taking into account the patients' age.
... Previously, using transcriptome sequencing (RNA-Seq), we have identified genes that are differentially expressed (DEGs) in the hypothalamus of hypertensive ISIAH rats versus control normotensive WAG rats, and among them, we identified genes associated with the hypertensive status of ISIAH rats and making the largest contribution to interstrain differences [33]. The aim of this work was to identify lncRNAs expressed in the hypothalamus of hypertensive ISIAH and normotensive WAG rats and coexpressed DEGs associated with hypertension and the behavior/neurological phenotype. ...
... The collected samples were sent to JSC Genoanalytica (Moscow, Russia), where RNA-Seq based on mRNA extraction was performed. The details of the protocol have been described earlier [33]. The obtained data were mapped to the RGSC Rnor_5.0\rn5.074 ...
... The upregulation of Cyp11b2 in the hypothalamus of ISIAH rats, which has previously been confirmed by qPCR [33], suggests that the excessive aldosterone synthesis in the hypothalamus of ISIAH rats may contribute to the pathogenesis of stress-sensitive hypertension and to the observed changes in behavior linked with increased anxiety in ISIAH rats. Because, as we demonstrated, Cyp11b2 expression correlates with LOC100910237 expression, we can theorize that lncRNA LOC100910237 is connected to these processes. ...
Long noncoding RNAs (lncRNAs) play an important role in the control of many physiological and pathophysiological processes, including the development of hypertension and other cardiovascular diseases. Nonetheless, the understanding of the regulatory function of many lncRNAs is still incomplete. This work is a continuation of our earlier study on the sequencing of hypothalamic transcriptomes of hypertensive ISIAH rats and control normotensive WAG rats. It aims to identify lncRNAs that may be involved in the formation of the hypertensive state and the associated behavioral features of ISIAH rats. Interstrain differences in the expression of seven lncRNAs were validated by quantitative PCR. Differential hypothalamic expression of lncRNAs LOC100910237 and RGD1562890 between hypertensive and normotensive rats was shown for the first time. Expression of four lncRNAs (Snhg4, LOC100910237, RGD1562890, and Tnxa-ps1) correlated with transcription levels of many hypothalamic genes differentially expressed between ISIAH and WAG rats (DEGs), including genes associated with the behavior/neurological phenotype and hypertension. After functional annotation of these DEGs, it was concluded that lncRNAs Snhg4, LOC100910237, RGD1562890, and Tnxa-ps1 may be involved in the hypothalamic processes related to immune-system functioning and in the response to various exogenous and endogenous factors, including hormonal stimuli. Based on the functional enrichment analysis of the networks, an association of lncRNAs LOC100910237 and Tnxa-ps1 with retinol metabolism and an association of lncRNAs RGD1562890 and Tnxa-ps1 with type 1 diabetes mellitus are proposed for the first time. Based on a discussion, it is hypothesized that previously functionally uncharacterized lncRNA LOC100910237 is implicated in the regulation of hypothalamic processes associated with dopaminergic synaptic signaling, which may contribute to the formation of the behavioral/neurological phenotype and hypertensive state of ISIAH rats.
... Considering the polygenic nature, it is of interest to identify and characterize genomic variants underlying predisposition to hypertension. Although numerous genome-wide association studies have been conducted to unravel the genetic basis of hypertension, the full picture is not yet clear [6][7][8][9][10][11][12]. A straightforward approach is to study likely functional variants in coding regions of hypertension-susceptibility genes. ...
Background:
Epoxide hydrolase 2 (EPHX2) gene coding for soluble epoxide hydrolase is a potential candidate in the pathogenesis of hypertension.
Objectives:
We aimed to assess the association of a missense mutation, R287Q, in EPHX2) gene coding for soluble epoxide hydrolase is a potential candidate in the pathogenesis of hypertension.
Methods:
This study involved 782 patients with primary hypertension and 458 healthy controls. Genotyping was done using TaqMan technique. Activity of soluble epoxide hydrolase fusion proteins was evaluated by the conversion of 11,12-EET to corresponding 11,12-DHET using ELISA kit.
Results:
After taking carriers of R287Q variant GG genotype as a reference, those with GA genotype had a significantly reduced risk of hypertension (adjusted odds ratio: 0.72, 95% confidence interval: 0.56 to 0.93, P = 0.013). Five significant risk factors were identified, including age, body mass index, total cholesterol, homocysteine, and R287Q variant. These five risk factors for hypertension were represented in a nomogram, with a descent prediction accuracy (C-index: 0.833, P = 0.013). Five significant risk factors were identified, including age, body mass index, total cholesterol, homocysteine, and R287Q variant. These five risk factors for hypertension were represented in a nomogram, with a descent prediction accuracy (C-index: 0.833.
Conclusions:
We provide evidence that R287Q mutation in EPHX2 gene was associated with reduced risk of primary hypertension and low activity of soluble epoxide hydrolase.EPHX2) gene coding for soluble epoxide hydrolase is a potential candidate in the pathogenesis of hypertension.
... Several developmental time series transcriptome datasets have been generated from different regions of the mammalian brain, such as cerebral cortex [19][20][21][22], hippocampus [23] and hypothalamus [24]. These datasets not only provide us the transcriptional landscape of different brain regions, neurodevelopmental processes, and potential causative factors for complex neurodevelopmental disorders, but can also be used to explore brain region-specific ontologies, cellular make-ups, and neurological processes. ...
Background:
The work of the FANTOM5 Consortium has brought forth a new level of understanding of the regulation of gene transcription and the cellular processes involved in creating diversity of cell types. In this study, we extended the analysis of the FANTOM5 Cap Analysis of Gene Expression (CAGE) transcriptome data to focus on understanding the genetic regulators involved in mouse cerebellar development.
Results:
We used the HeliScopeCAGE library sequencing on cerebellar samples over 8 embryonic and 4 early postnatal times. This study showcases temporal expression pattern changes during cerebellar development. Through a bioinformatics analysis that focused on transcription factors, their promoters and binding sites, we identified genes that appear as strong candidates for involvement in cerebellar development. We selected several candidate transcriptional regulators for validation experiments including qRT-PCR and shRNA transcript knockdown. We observed marked and reproducible developmental defects in Atf4, Rfx3, and Scrt2 knockdown embryos, which support the role of these genes in cerebellar development.
Conclusions:
The successful identification of these novel gene regulators in cerebellar development demonstrates that the FANTOM5 cerebellum time series is a high-quality transcriptome database for functional investigation of gene regulatory networks in cerebellar development.
... The overexpression of Ephx2 also may reduce the amount of EETs as they are hydrolyzed by sEH [47]. So, the changes in the arachidonic acid metabolic pathways may have significant impact to ISIAH brain stem function, and the Ephx2 gene may be considered as a key one as its strong contribution to the inter-strain differences was also shown in the studies of hypothalamus, adrenal gland and kidney of the ISIAH and WAG rats [49][50][51][52]. ...
... An increased level of Ephx2 transcription was found in several tissues/organs (brain stem, hypothalamus, adrenal gland and kidney) of ISIAH rats compared to WAG rats [49][50][51][52]. However, SNPs were not identified in the Ephx2 mRNA sequence in ISIAH rats. ...
... Taking our results into account, we would like to conclude that the study revealed multiple DEGs in brain stem of hypertensive ISIAH and normotensive WAG rats and underlined the most important biological processes and pathways related to stress-sensitive hypertension. These results confirmed the complex nature of the pathogenesis of hypertension in the ISIAH rats, which was earlier demonstrated in the comparative studies of transcriptional profiling of other target tissues/organs (hypothalamus, adrenal gland and kidney) from ISIAH and WAG rats [49][50][51][52]. Gene Ephx2 may be considered as a major candidate gene, as it was defined as one, making the most contribution to the inter-strain differences not only in the brain stem of ISIAH rats but also in all other analyzed tissues/organs (hypothalamus, adrenal gland and kidney) known as targets in hypertension development [49][50][51][52]. ...
Background
The development of essential hypertension is associated with a wide range of mechanisms. The brain stem neurons are essential for the homeostatic regulation of arterial pressure as they control baroreflex and sympathetic nerve activity. The ISIAH (Inherited Stress Induced Arterial Hypertension) rats reproduce the human stress-sensitive hypertensive disease with predominant activation of the neuroendocrine hypothalamic-pituitary-adrenal and sympathetic adrenal axes. RNA-Seq analysis of the brain stems from the hypertensive ISIAH and normotensive control WAG (Wistar Albino Glaxo) rats was performed to identify the differentially expressed genes (DEGs) and the main central mechanisms (biological processes and metabolic pathways) contributing to the hypertensive state in the ISIAH rats.
Results
The study revealed 224 DEGs. Their annotation in databases showed that 22 of them were associated with hypertension and blood pressure (BP) regulation, and 61 DEGs were associated with central nervous system diseases. In accordance with the functional annotation of DEGs, the key role of hormonal metabolic processes and, in particular, the enhanced biosynthesis of aldosterone in the brain stem of ISIAH rats was proposed. Multiple DEGs associated with several Gene Ontology (GO) terms essentially related to modulation of BP were identified. Abundant groups of DEGs were related to GO terms associated with responses to different stimuli including response to organic (hormonal) substance, to external stimulus, and to stress. Several DEGs making the most contribution to the inter-strain differences were detected including the Ephx2, which was earlier defined as a major candidate gene in the studies of transcriptional profiles in different tissues/organs (hypothalamus, adrenal gland and kidney) of ISIAH rats.
Conclusions
The results of the study showed that inter-strain differences in ISIAH and WAG brain stem functioning might be a result of the imbalance in processes leading to the pathology development and those, exerting the compensatory effects. The data obtained in this study are useful for a better understanding of the genetic mechanisms underlying the complexity of the brain stem processes in ISIAH rats, which are a model of stress-sensitive form of hypertension.
... 45,46 The enhanced expression of the Ephx2 gene in the hypertensive hypothalamus might therefore lead to a reduced amount of EETs and be conducive to the development of hypertension in SH rats. 47 In turn, the Ephx2 gene in the hypothalamus was significantly decreased in the Renying (ST 9) group compared with the model group. Clinical studies have shown that acupuncture can exert a protective effect against the production and expression of inflammatory cytokines and adhesion molecules, effectively blocking the inflammatory reaction and reducing BP. ...
Objective
To investigate changes in gene expression profiles in the hypothalamus related to the effects of acupuncture at the Renying (ST 9) acupoint in spontaneously hypertensive (SH) rats.
Methods
We randomly divided 18 SH rats into Renying (ST 9) group and model control group, 9 body weight-matched Wistar-Kyoto rats were used as blank controls. Acupuncture was performed manually for 20-min daily over 28 d in the Renying (ST 9) group. Rat Gene 2.0 array technology was used for the determination of gene expression profiles and the screened key genes were verified by real-time quantitative polymerase chain reaction (RT-PCR) analyses.
Results
The different groups exhibited differential gene expression: compared with the blank control group, 48 genes were up-regulated and 91 genes were down-regulated in the model group; compared with the model group, 79 genes were up-regulated and 80 genes were down-regulated in Renying (ST 9) group. The RT-PCR results of the key genes including Chi3l1, Ephx2, Klk1, 5-HT1A and Cbs were consistent with that of gene chip analysis.
Conclution
Acupuncture at Renying (ST 9) could significantly lower the blood pressure of SH rats and affect their hypothalamic gene expression profile. Genes associated with the contraction of vascular smooth muscle and the regulation of inflammation, neurotransmitters may be involved in acupuncture's antihypertensive mechanism.
... Multiple DEGs associated with GO term 'immune system process' are annotated in RGD as associated with hypertension. The important role of inflammation and immunity in development of the stress-sensitive hypertension was already highlighted in our previous comparative studies of genome-wide transcriptome analyses of hypothalamus and renal cortex from ISIAH and WAG rats [63,64]. A growing body of research supporting a role of inflammation and immunity in hypertension was recently summarized in multiple reviews [65][66][67][68][69][70][71][72]. ...
Background
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. ResultsThe 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. Conclusions
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 ISIAH rat strain (Inherited stress-induced arterial hypertension) was developed by selection for high systolic arterial blood pressure (SABP) induced by restraint stress. Earlier studies showed that the ISIAH rats may be considered as a model of the human stress sensitive hypertensive disease with predominant involvement of the neuroendocrine hypothalamic-pituitary-adrenal (HPA) and sympathoadrenal systems in the pathogenesis of the hypertensive state [7].The studies of the genetic background underlying the stress-sensitive hypertension in the ISIAH rats were already published in special issues of BMC Genetics after BGRS\SB-2014 and SBB-2015 events [8][9][10]. Current paper outlines the results of the geneexpression profiling in renal medulla of the ISIAH rats and reveal the genes which affect renal function and the long-term control of arterial blood pressure are discussed. ...
