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D Krenova

Publications and source records attributed to D Krenova.

13 recordsLinked to original sources
PubMed2004

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome.

OBJECTIVE: To investigate the effect of transcription-modulating drugs, fenofibrate and isotretinoin, on metabolic profile, insulin sensitivity of adipose and muscle tissues and gene expression in a genetic model of insulin resistance syndrome, polydactylous rat strain (PD/Cub). DESIGN: Administration of fenofibrate (100 mg/kg/day), isotretinoin (30 mg/kg/day) or vehicle to adult male PD/Cub rats fed standard laboratory chow for 15 days. MEASUREMENTS: Parameters of lipid and carbohydrate metabolism-oral glucose tolerance test, serum concentrations of insulin, triglycerides (TG), free fatty acids (FFA), glycerol, total cholesterol (CH); morphometric variables, in vitro insulin sensitivity of adipose and muscle tissues, catecholamine-stimulated lipolysis and the expression of ApoC-III and Hnf-4 genes in liver. RESULTS: Both experimental groups displayed an increase in adiposity with contrasting effects on TG (lowered by fenofibrate and increased by isotretinoin) and gene expression (no change in fibrate-treated rats and increased expression of ApoC-III and Hnf-4 in isotretinoin-treated group). Fenofibrate-treated rats also showed decreased concentrations of FFA and CH with concomitant decrease of catecholamine-induced lipolysis in adipocytes, but also hyperinsulinemia and the highest insulin/glucose ratio. Isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues. CONCLUSION: The PD/Cub rat showed a distinct pharmacogenetic reaction to fenofibrate and isotretinoin administration. Several lines of evidence now implicate specific variant(s) of ApoC-III and/or ApoA-V alleles as responsible for the dyslipidemia observed in this genetic model. The PD/Cub strain may also serve as a pharmacogenetic model for dissection of the retinoid-induced hypertriglyceridemia.

Adipose Tissue↗
PubMed2001

Y-chromosome transfer induces changes in blood pressure and blood lipids in SHR.

Previous studies with chromosome-Y consomic strains of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats suggest that a quantitative trait locus for blood pressure regulation exists on chromosome Y. To test this hypothesis in the SHR-Brown Norway (BN) model and to study the effects of chromosome Y on lipid and carbohydrate metabolism, we produced a new consomic strain of SHR carrying the Y chromosome transferred from the BN rat. We found that replacing the SHR Y chromosome with the BN Y chromosome resulted in significant decreases in systolic and diastolic blood pressures in the SHR.BN-Y consomic strain (P<0.05). To elicit possible dietary-induced variation in lipid and glucose metabolism between the SHR progenitor and chromosome-Y consomic strains, we fed rats a high-fructose diet for 15 days in addition to the normal diet. On the high-fructose diet, the SHR.BN-Y consomic rats exhibited significantly increased levels of serum triglycerides and decreased levels of serum HDL cholesterol versus the SHR progenitor rats. Glucose tolerance and insulin/glucose ratios, however, were similar in both strains on both normal and high-fructose diets. These findings provide direct evidence that a gene or genes on chromosome Y contribute to the pathogenesis of spontaneous hypertension in the SHR-BN model. These results also indicate that transfer of the Y chromosome from the BN rat onto the SHR background exacerbates dietary-induced dyslipidemia in SHR. Thus, genetic variation in genes on the Y chromosome may contribute to variation in blood pressure and lipid levels and may influence the risk for cardiovascular disease.

Animals↗
PubMed2000

Mapping of quantitative trait loci (QTL) of differential stress gene expression in rat recombinant inbred strains.

OBJECTIVE: Stress has been shown to be a major environmental contributor to cardiovascular diseases through its effects on blood pressure variability and cardiac function. The cellular stress response is characterized by the expression of specific heat stress genes (hsps), under the transcriptional control of heat shock transcription factors (HSTFs). The levels of hsp mRNA depend on the severity of the stress, with hstf1 acting as a stress sensor. The aim of this work was to evaluate the genetic contribution of the variability in hsp expression, and to identify its putative quantitative trait loci (QTL). METHODS: Twenty recombinant inbred rat strains (RIS) were studied. The animals underwent a standardized, identical 1 h immobilization stress in restraint cages, followed by 1 h of rest before sacrifice. Total RNA was extracted from the heart kidneys and adrenals, and the mRNA levels of hsp27, hsp70, hsp84, hsp86 and hsp105 were measured. The strain distribution pattern (SDP) of hsp expression was correlated with that of 475 polymorphic markers distributed throughout the RIS genome. A polymorphism of rat hstf1 in RIS was used for its mapping in RIS. RESULTS: Despite an identical stress being applied to all strains, hsp expression showed up to a 1 2-fold gradient with little intra-strain variability, indicative of a strong genetic contribution to the trait Heritability ranged from 50 to 77% for most hsp genes in the three target organs. The continuous SDP of stress gene expression indicated the polygenic nature of the trait A common locus on chromosome 7 (at D7Cebrp187s3 marker) was consistently associated with all hsp expression in most of the organs [with a likelihood of odds (LOD) score of 3.0 for hsp27 expression]. We have mapped rat hstf1 on chromosome 7 at the same locus. Finally, the D4Mit19 marker was significantly associated with hsp84 expression in the heart (LOD score of 3.1). CONCLUSION: Two loci were linked with the differential expression of HSPs in response to immobilization stress in target organs of RIS. The chromosome 7 locus unveiled for all HSPs could explain up to 42% of the observed inter-strain variability of hsp levels in response to stress. We propose hstf1 as a positional candidate at this locus.

Adrenal Glands↗
PubMed1999

Effect of chromosome 19 transfer on blood pressure in the spontaneously hypertensive rat.

Linkage studies in the spontaneously hypertensive rat (SHR) have suggested that a gene or genes regulating blood pressure may exist on rat chromosome 19 in the vicinity of the angiotensinogen gene. To test this hypothesis, we measured blood pressure in SHR progenitor and congenic strains that are genetically identical except for a segment of chromosome 19 containing the angiotensinogen gene transferred from the normotensive Brown Norway (BN) strain. Transfer of this segment of chromosome 19 from the BN strain onto the genetic background of the SHR induced significant decreases in systolic and diastolic blood pressures in the recipient SHR chromosome 19 congenic strain. To test for differences in angiotensinogen gene expression between the congenic and progenitor strains, we measured angiotensinogen mRNA levels in a variety of tissues, including aorta, brain, kidney, and liver. We found no differences between the progenitor and congenic strains in the angiotensinogen coding sequence or in angiotensinogen expression that would account for the blood pressure differences between the strains. In addition, no significant differences in plasma levels of angiotensinogen or plasma renin activity were detected between the 2 strains. Thus, transfer of a segment of chromosome 19 containing angiotensinogen from the BN rat into the SHR induces a decrease in blood pressure without inducing any major changes in plasma angiotensinogen levels or plasma renin activity. These results indicate that the differential chromosome segment trapped in the SHR chromosome 19 congenic strain contains a quantitative trait locus that influences blood pressure in the SHR but that this blood pressure effect is not explained by differences in plasma angiotensinogen levels or angiotensinogen expression.

Angiotensinogen↗
PubMed1999

Genetics of Cd36 and the clustering of multiple cardiovascular risk factors in spontaneous hypertension.

Disorders of carbohydrate and lipid metabolism have been reported to cluster in patients with essential hypertension and in spontaneously hypertensive rats (SHRs). A deletion in the Cd36 gene on chromosome 4 has recently been implicated in defective carbohydrate and lipid metabolism in isolated adipocytes from SHRs. However, the role of Cd36 and chromosome 4 in the control of blood pressure and systemic cardiovascular risk factors in SHRs is unknown. In the SHR. BN-Il6/Npy congenic strain, we have found that transfer of a segment of chromosome 4 (including Cd36) from the Brown Norway (BN) rat onto the SHR background induces reductions in blood pressure and ameliorates dietary-induced glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. These results demonstrate that a single chromosome region can influence a broad spectrum of cardiovascular risk factors involved in the hypertension metabolic syndrome. However, analysis of Cd36 genotypes in the SHR and stroke-prone SHR strains indicates that the deletion variant of Cd36 was not critical to the initial selection for hypertension in the SHR model. Thus, the ability of chromosome 4 to influence multiple cardiovascular risk factors, including hypertension, may depend on linkage of Cd36 to other genes trapped within the differential segment of the SHR. BN-Il6/Npy strain.

Animals↗
PubMed1998

Newborn and adult recombinant inbred strains: a tool to search for genetic determinants of target organ damage in hypertension.

It has been proposed that one of the primary events in the development of essential hypertension is a growth-related process initiated as early as during fetal development. Differences in kidney size have been observed between most rat models of hypertension and their respective controls. In this study, we analyzed relative kidney size (kidney weight/body wt) in a set of rat recombinant inbred strains (RIS) (N = 27) and their progenitors, the spontaneously hypertensive rat strain (SHR/Ola) and Brown Norway congenic strain (BN.1x), at two different ages, at birth and at 15 weeks. In the progenitors, the relative kidney weight was higher in the hypertensive than in the normotensive strain of both the newborn (P < 0.001) and adult (P < 0.001) animals. In the RIS, a significant correlation was found between the newborn and adult relative kidney weight (r = 0.49, P = 0.01), indicating that the two phenotypes share some of their genetic determinants. A total genome search of newborn and adult relative kidney weight was performed with a total of 453 genetic markers. These analyses revealed several suggestive quantitative trait loci (QTL), some of which were, indeed, significant for both newborn and adult relative kidney weight (such as, D3Mit9 on rat chromosome 3; r = -0.50, P < 0.01; r = -0.47, P < 0.01; respectively). Others, such as the locus on rat chromosome 1 (Rt6; r = -0.43, P < 0.05), were significant only for the adult relative kidney size. This QTL was found in close proximity to a region previously related to susceptibility to hypertensive renal disease in the fawn-hooded rat and, similarly to that study, its effect was found to be independent of blood pressure. Furthermore, a growth pattern of the kidneys after birth, evaluated as the difference between the newborn and adult relative kidney weight, was also subjected to total genome scan. Several suggestive QTL were identified. One of the most significant loci was found at the D1a marker on rat chromosome 17 (r = -0.51, P < 0.01), which was previously related to the determination of adult heart weight in the RIS. In conclusion, the current study demonstrates the usefulness of RIS in studies of hypertension-related phenotypes, some of which are abnormal before the development of high blood pressure. To better understand their role in the pathogenesis of hypertension, studies at different ages are needed, which are uniquely feasible in RIS.

Aging↗
PubMed1998

Effect of renin gene transfer on blood pressure in the spontaneously hypertensive rat.

To investigate whether molecular variation in the renin gene contributes to the greater blood pressure of spontaneously hypertensive rats (SHR) versus normotensive Brown Norway (BN) rats, we measured blood pressure in an SHR progenitor strain and an SHR congenic strain that are genetically identical except at the renin gene and an associated segment of chromosome 13 transferred from the BN strain. Backcross breeding and molecular selection at the renin locus were used to create the SHR congenic strain (designated SHR.BN-Ren) that carries the renin gene transferred from the normotensive BN strain. We found that transfer of the renin gene from the BN strain onto the genetic background of the SHR did not decrease blood pressure in rats fed either a normal or high-salt diet. In fact, the systolic blood pressures of the SHR congenic rats tended to be slightly greater than the systolic blood pressures of the SHR progenitor rats. However, the congenic strain exhibited lower serum high-density lipoprotein cholesterol, and greater levels of total cholesterol, very-low-density lipoprotein, and intermediate-density lipoprotein cholesterol during administration of a high-fat, high-cholesterol diet. These findings demonstrate that (1) under the environmental circumstances of the current study, the greater blood pressure of SHR versus BN rats cannot be explained by strain differences in the renin gene and (2) a quantitative trait locus affecting lipid metabolism exists on chromosome 13 within the transferred chromosome segment. The SHR.BN-Ren congenic strain may provide a useful new animal model for studying the interaction between high blood pressure and dyslipidemia in cardiovascular disease.

Animals↗
PubMed1997

Genetic isolation of a region of chromosome 8 that exerts major effects on blood pressure and cardiac mass in the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) is the most widely studied animal model of essential hypertension. Despite > 30 yr of research, the primary genetic lesions responsible for hypertension in the SHR remain undefined. In this report, we describe the construction and hemodynamic characterization of a congenic strain of SHR (SHR-Lx) that carries a defined segment of chromosome 8 from a normotensive strain of Brown-Norway rats (BN-Lx strain). Transfer of this segment of chromosome 8 from the BN-Lx strain onto the SHR background resulted in substantial reductions in systolic and diastolic blood pressure and cardiac mass. Linkage and comparative mapping studies indicate that the transferred chromosome segment contains a number of candidate genes for hypertension, including genes encoding a brain dopamine receptor and a renal epithelial potassium channel. These findings demonstrate that BP regulatory gene(s) exist within the differential chromosome segment trapped in the SHR-Lx congenic strain and that this region of chromosome 8 plays a major role in the hypertension of SHR vs. BN-Lx rats.

Animals↗
PubMed1997

Mapping genes controlling hematocrit in the spontaneously hypertensive rat.

The genes that determine the baseline hematocrit level in humans and experimental animals are unknown. The spontaneously hypertensive rat (SHR), the most widely used animal model of human essential hypertension, exhibits an increased hematocrit when compared with the normotensive Brown Norway (BN-Lx) strain (0.54 +/- 0.02 vs. 0.44 +/- 0.02, p < 0.01). Distribution of hematocrit values among recombinant inbred (RI) strains derived from SHR and BN-Lx progenitors was continuous, which suggests a polygenic mode of inheritance. The narrow heritability of the hematocrit was estimated to be 0.32. The Eno2 marker on Chromosome (Chr) 4 showed the strongest association (p < 0.0001) with the observed variability of hematocrit among RI strains. The erythropoietin (Epo) gene, originally reported to be syntenic with Eno2, has been mapped to Chr 12, thus excluding it as a potential candidate gene for the increased hematocrit in the SHR. The current linkage data extend homologies between rat, mouse, and human chromosomes.

Animals↗
PubMed1997

Genetic isolation of a chromosome 1 region affecting blood pressure in the spontaneously hypertensive rat.

Recent linkage studies in the spontaneously hypertensive rat (SHR) suggest that a blood pressure regulatory gene or genes may be located on rat chromosome 1q. To investigate this possibility, we replaced a region of chromosome 1 in the SHR (defined by the markers D1Mit3 and Igf2) with the corresponding chromosome segment from the normotensive Brown-Norway (BN) strain. In male SHR congenic rats carrying the transferred BN chromosome segment, 24-hour average systolic and diastolic blood pressures were significantly lower than in male progenitor SHR. Polymerase chain reaction genotyping using 60 polymorphic microsatellite markers dispersed throughout the genome confirmed the congenic status of the new strain designated SHR.BN-D1Mit3/Igf2. These findings provide direct evidence that a blood pressure regulatory gene exists on the differential segment of chromosome 1 that is sufficient to decrease blood pressure in the SHR. The SHR.BN-D1Mit3/Igf2 congenic strain represents an important new model for fine mapping and characterization of genes on chromosome 1 involved in the pathogenesis of spontaneous hypertension.

Animals↗