S. E. Smolenskaya

Differential transcriptional activity of kidney genes in hypertensive ISIAH and normotensive WAG rats.

Abstract Transcriptional activity of the kidney genes was compared in hypertensive ISIAH and normotensive WAG rats using the oligonucleotide microarray technique. Most of differentially expressed genes were downregulated in ISIAH kidney both in renal cortex and medulla. According to functional annotation the kidney function in ISIAH rats is based on altered expression of many genes working in stress-related mode. The alterations in gene expression are likely related to both pathophysiological and compensatory mechanisms. The further studies of genes differentially expressed in ISIAH and WAG kidney will help to reveal new hypertensive genes and mechanisms specific for stress-induced arterial hypertension.

The Genetic Control of Blood Pressure and Body Composition in Rats with Stress-Sensitive Hypertension

The genetic basis of the stress-sensitive arterial hypertension was investigated using the quantitative trait loci (QTL) approach. Two groups of F2 (inherited stress-induced arterial hypertension [ISIAH] × Wistar albino Glaxo [WAG]) hybrid males of different age (3–4 months old and 6 months old) were tested for blood pressure at rest and stressed conditions and for body composition traits. Several novel loci for the traits were determined. Some loci for blood pressure and organ weight were mapped to the same genetic region in rats of different age. The dynamic change of QTL effects in two rat groups of different age might reflect the process of stress-sensitive hypertension development.

Elevated expression of the Ephx2 mRNA in the kidney of hypertensive ISIAH rats

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.

Genetic Control of the Corticosterone Level at Rest and Under Emotional Stress in ISIAH Rats with Inherited Stress-Induced Arterial Hypertension

The genetic background of the regulatory systems of the hypothalamic-pituitary-adrenal (HPA) axis in hypertension remains unclear. The inherited stress-induced arterial hypertension (ISIAH) and Wistar Albino Glaxo (WAG) normotensive rats were bred and their F2 progeny were used in a quantitative trait loci (QTL) analysis to identify genomic regions for plasma basal and stress-induced corticosterone levels, and for absolute and relative adrenal gland weights. The significant loci were found for stress-induced corticosterone on chromosome 9 and for adrenal weight on chromosome 6. The results may help to identify the genes controlling the trait phenotypes in the ISIAH rats characterized by the enhanced responsiveness to stressful stimulation.

Genetic loci for spleen weight and blood pressure in ISIAH rats with inherited stress-induced arterial hypertension

Recently, the important role of the spleen’s function in hypertension development was demonstrated. In this study, the genetic control of absolute and relative spleen weight was investigated to reveal the genetic loci common for spleen traits and for arterial blood pressure at rest and under the emotional stress conditions in ISIAH rats with inherited stress-induced arterial hypertension. The search for genetic loci for absolute and relative spleen weight was performed on 6-month-old F2 (ISIAH × WAG) hybrid males derived from a cross of hypertensive ISIAH and normotensive WAG rats. One significant QTL mapped on chromosome 1 and 5 suggestive loci were found for relative spleen weight. Four suggestive loci were detected for absolute spleen weight. All detected loci were novel. The significant QTL on chromosome 1 was common for relative spleen weight and arterial blood pressure at rest and under the emotional stress conditions in ISIAH rats. The results suggest that the manifestation of the stress-sensitive arterial hypertension in ISIAH rats may be related to the changes in genetic control of the spleen function.

Soluble epoxide hydrolase (sEH) as a potential target for arterial hypertension therapy

Using ISIAH rat strain, an animal model for stress-sensitive form of arterial hypertension, a comparison of the brain stem, hypothalamus, adrenal gland, and kidney transcriptomes for identification of the key genes involved in the development of the stress-sensitive form of arterial hypertension was conducted. Our studies revealed Ephx2 gene encoding soluble epoxide hydrolase (sEH), whose transcription level was significantly higher in all the examined organs. On the basis of other studies and our previous investigations, we concluded the necessity of further studies of Ephx2 gene and an encoded sEH protein as a potential target for pharmacological treatment of stress-sensitive arterial hypertension.

Expression of catechol-O-methyltransferase (Comt), mineralocorticoid receptor (Mlr), and epithelial sodium channel (ENaC) genes in kidneys of hypertensive ISIAH rats at rest and during response to stress

Emotional stress plays a significant role in the processes of the development of arterial hypertension, especially in the presence of genetic predisposition. The origin and maintenance of hypertensive status during stress development can be activated by the sympathetic nervous system. An increase in sympathetic stimulation can, in turn, result in a change in the functions of kidneys, which provide fluid and electrolyte balance of the organism. A comparative study of the mRNA expression level of catechol-o-methyltransferase (Comt), mineralocorticoid receptor (Mlr), and β-subunit of epithelial sodium channel (β-ENaC) genes was conducted on the kidneys of hypertensive ISIAH rats and normotensive WAG rats at rest and after the effect of emotional stress. The discovered changes in the expression level of the selected genes confirm their involvement in increased sympathetic stimulation of the kidney, along with changes in the function of kidney regulation of fluid and electrolyte balance, which is an important factor of the development of sustained hypertension in the ISIAH rats strain.

Differentially expressed genes in the locus associated with relative kidney weight and resting blood pressure in hypertensive rats of the ISIAH strain

The comparative full-genome sequencing of transcriptomes of the renal cortex and medulla from hypertensive ISIAH rats and normotensive WAG rats revealed the differential expression of genes in the locus of chromosome 11 associated to the traits of resting blood pressure and relative kidney weight. Six differentially expressed genes (Kcne1, Rcan1, Mx1, Mx2, Tmprss2, and RGD1559516) were identified in the renal cortex, and three genes (Rcan1, Mx2, and Tmprss2) were identified in the renal medulla. An analysis of the functions of these genes pointed at the Rcan1 gene as the most relevant candidate gene associated with both the traits of resting blood pressure and relative kidney weight in ISIAH rats. The elevation of the transcription levels of the Mx1 and Mx2 genes in hypertensive ISIAH rats may represent an adaptation that contributes to the alleviation of inflammatory processes in the kidneys.