scholarly journals Genetically Determined Folate Deficiency Is Associated With Abnormal Hepatic Folate Profiles in the Spontaneously Hypertensive Rat

2018 ◽  
pp. 417-422 ◽  
Author(s):  
M. PRAVENEC ◽  
K.-Y. LEUNG ◽  
V. ZÍDEK ◽  
P. MLEJNEK ◽  
M. ŠIMÁKOVÁ ◽  
...  
Keyword(s):  
Congenic Strain ◽  
Spontaneously Hypertensive Rat ◽  
Folate Receptor ◽  
Whole Body ◽  
Wild Type ◽  
Metabolic Disturbances ◽  
Lower Plasma ◽  
Spontaneously Hypertensive ◽  
Genetically Determined ◽  
Relationship Of

Increased levels of plasma cysteine are associated with obesity and metabolic disturbances. Our recent genetic analyses in spontaneously hypertensive rats (SHR) revealed a mutated Folr1 (folate receptor 1) as the quantitative trait gene associated with diminished renal Folr1 expression, lower plasma folate levels, hypercysteinemia, hyperhomocysteinemia and metabolic disturbances. To further analyse the effects of the Folr1 gene expression on folate metabolism, we used mass spectrometry to quantify folate profiles in the plasma and liver of an SHR-1 congenic strain, with wild type Folr1 allele on the SHR genetic background, and compared them with the SHR strain. In the plasma, concentration of 5-methyltetrahydrofolate (5mTHF) was significantly higher in SHR-1 congenic rats compared to SHR (60±6 vs. 42±2 nmol/l, P<0.01) and 5mTHF monoglutamate was the predominant form in both strains (>99 % of total folate). In the liver, SHR-1 congenic rats showed a significantly increased level of 5mTHF and decreased concentrations of dihydrofolate (DHF), tetrahydrofolate (THF) and formyl-THF when compared to the SHR strain. We also analysed the extent of folate glutamylation in the liver. Compared with the SHR strain, congenic wild-type Folr1 rats had significantly higher levels of 5mTHF monoglutamate. On the other hand, 5mTHF penta- and hexaglutamates were significantly higher in SHR when compared to SHR-1 rats. This inverse relationship of rat hepatic folate polyglutamate chain length and folate sufficiency was also true for other folate species. These results strongly indicate that the whole body homeostasis of folates is substantially impaired in SHR rats compared to the SHR-1 congenic strain and might be contributing to the associated metabolic disturbances observed in our previous studies.

scholarly journals Genetic architecture of Wistar-Kyoto rat and spontaneously hypertensive rat substrains from different sources

2013 ◽  
Vol 45 (13) ◽  
pp. 528-538 ◽  
Author(s):  
Yanli Zhang-James ◽  
Frank A. Middleton ◽  
Stephen V. Faraone
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Wistar Rat ◽  
Spontaneously Hypertensive ◽  
Hypertensive Rat ◽  
Genome Wide ◽  
Daunting Task ◽  
History Of ◽  
Wistar Kyoto ◽  
Complex Relationships ◽  
Relationship Of

The spontaneously hypertensive rat (SHR) has been widely used as a model for studies of hypertension and attention deficit/hyperactivity disorder. The inbred Wistar-Kyoto (WKY) rat, derived from the same ancestral outbred Wistar rat as the SHR, are normotensive and have been used as the closest genetic control for the SHR, although the WKY has also been used as a model for depression. Notably, however, substantial behavioral and genetic differences among the WKY substrains, usually from the different vendors and breeders, have been observed. These differences have often been overlooked in prior studies, leading to inconsistent and even contradictory findings. The complicated breeding history of the SHR and WKY rats and the lack of a comprehensive understanding of the genetic background of different commercial substrains make the selection of control rats a daunting task, even for researchers who are mindful of their genetic heterogeneity. In this study, we examined the genetic relationship of 16 commonly used WKY and SHR rat substrains using genome-wide SNP genotyping data. Our results confirmed a large genetic divergence and complex relationships among the SHR and WKY substrains. This understanding, although incomplete without the genome sequence, provides useful guidance in selecting substrains and helps to interpret previous reports when the source of the animals was known. Moreover, we found two closely related, yet distinct WKY substrains that may provide novel opportunities in modeling psychiatric disorders.

scholarly journals Refractory blood pressure in female SHR to increased oxidative stress is not mediated by NO or by upregulation of renal antioxidant enzymes

2010 ◽  
Vol 298 (2) ◽  
pp. R266-R271 ◽  
Author(s):  
Arnaldo F. Lopez-Ruiz ◽  
Radu Iliescu ◽  
Jane F. Reckelhoff
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Antioxidant Enzymes ◽  
Sex Difference ◽  
Spontaneously Hypertensive Rat ◽  
Pressor Response ◽  
Whole Body ◽  
Spontaneously Hypertensive ◽  
Endogenous Nitric Oxide ◽  
Wistar Kyoto

There is a sex difference in the blood pressure (BP) responses to prooxidants and antioxidants in the spontaneously hypertensive rat (SHR). In contrast to males, BP in female SHR does not decrease in response to antioxidants, such as tempol or apocynin, or increase in response to the prooxidant, molsidomine. Molsidomine decreases BP and increases expression of antioxidants in male Wistar-Kyoto rats (WKY), but not male SHR. The present study tested the hypothesis that the mechanism responsible for the lack of a pressor response to molsidomine in females is due to higher endogenous nitric oxide (NO) or to compensatory upregulation of renal antioxidant enzymes. Female SHR were treated with molsidomine in the presence or absence of nitro-l-arginine methyl ester (l-NAME) for 2 wk. Molsidomine increased nitrate/nitrite (NOx) and F2-isoprostane (F2-IsoP) excretion, whereas l-NAME reduced NOx but increased F-Isop. Molsidomine and l-NAME together further reduced NOx and increased F2-IsoP. Molsidomine alone had no effect on BP; l-NAME alone increased BP. The combination of molsidomine and l-NAME did not increase BP above l-NAME alone levels. Whole body and renal oxidative stress increased, while renal cortical Cu,Zn-SOD expression was downregulated and catalase was upregulated by molsidomine; glutathione peroxidase expression was unaffected. These data support our previous studies suggesting that BP in female SHR is independent of either increases or decreases in oxidative stress. The mechanisms responsible for the sex difference in BP response to increase or decrease of oxidative stress are not due to increased NO in females or to compensatory upregulation of antioxidant enzymes in response to increases in oxidants.

scholarly journals Recent Progress in the Genetics of Spontaneously Hypertensive Rats

2014 ◽  
pp. S1-S8 ◽  
Author(s):  
M. PRAVENEC ◽  
V. KŘEN ◽  
V. LANDA ◽  
P. MLEJNEK ◽  
A. MUSILOVÁ ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Regulation Of Gene Expression ◽  
Data Sets ◽  
Metabolic Disturbances ◽  
Spontaneously Hypertensive ◽  
Quantitative Metabolomics ◽  
Multiple Data ◽  
Multiple Data Sets ◽  
Functional Analyses

The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and accompanying metabolic disturbances. Recent advances in sequencing of genomes of BN-Lx and SHR progenitors of the BXH/HXB recombinant inbred (RI) strains as well as accumulation of multiple data sets of intermediary phenotypes in the RI strains, including mRNA and microRNA abundance, quantitative metabolomics, proteomics, methylomics or histone modifications, will make it possible to systematically search for genetic variants involved in regulation of gene expression and in the etiology of complex pathophysiological traits. New advances in manipulation of the rat genome, including efficient transgenesis and gene targeting, will enable in vivo functional analyses of selected candidate genes to identify QTL at the molecular level or to provide insight into mechanisms whereby targeted genes affect pathophysiological traits in the SHR.

Novel double-congenic strain reveals effects of spontaneously hypertensive rat chromosome 2 on specific lipoprotein subfractions and adiposity

2006 ◽  
Vol 27 (1) ◽  
pp. 95-102 ◽  
Author(s):  
Ondřej Šeda ◽  
Lucie Šedová ◽  
František Liška ◽  
Drahomíra Křenová ◽  
Vratislav Prejzek ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Glucose Intolerance ◽  
Congenic Strain ◽  
Spontaneously Hypertensive Rat ◽  
Density Lipoprotein ◽  
Chromosome 2 ◽  
Lipoprotein Subfractions ◽  
Spontaneously Hypertensive ◽  
Hypertensive Rat ◽  
Rat Strain

We have developed a new, double-congenic rat strain BN- Lx.SHR2, which carries two distinct segments of chromosome 2 introgressed from the spontaneously hypertensive rat strain (SHR) into the genetic background of congenic strain BN- Lx, which was previously shown to express variety of metabolic syndrome features. In 16-wk-old male rats of BN- Lx and BN- Lx.SHR2 strains, we compared their glucose tolerance and triacylglycerol and cholesterol concentrations in 20 lipoprotein subfractions and the lipoprotein particle sizes under conditions of feeding standard and high-sucrose diets. Introgression of two distinct SHR-derived chromosome 2 segments resulted in decreased adiposity together with aggravation of glucose intolerance in the double-congenic strain. The BN- Lx.SHR2 rats were more sensitive to sucrose-induced rise in triacylglycerolemia. Although the total cholesterol concentrations of the two strains were comparable after the standard diet and even lower in BN- Lx.SHR2 after sucrose feeding, detailed analysis revealed that under both dietary conditions, the double-congenic strain had significantly higher cholesterol concentrations in low-density lipoprotein fractions and lower high-density lipoprotein fractions. We established a new inbred model showing dyslipidemia and mild glucose intolerance without obesity, attributable to specific genomic regions. For the first time, the chromosome 2 segments of SHR origin are shown to influence other than blood pressure-related features of metabolic syndrome or to be involved in relevant nutrigenomic interactions.

scholarly journals Gender-Related Effects on Substrate Utilization and Metabolic Adaptation in Hairless Spontaneously Hypertensive Rat

2015 ◽  
pp. 51-60 ◽  
Author(s):  
J. TRNOVSKÁ ◽  
J. ŠILHAVÝ ◽  
V. ZÍDEK ◽  
M. ŠIMÁKOVÁ ◽  
P. MLEJNEK ◽  
...  
Keyword(s):  
Insulin Action ◽  
Spontaneously Hypertensive Rat ◽  
Interaction Effects ◽  
Metabolic Adaptation ◽  
Wild Type ◽  
Spontaneously Hypertensive ◽  
Palmitate Oxidation ◽  
Muscle Tissues ◽  
Brown Adipose ◽  
Glucose Incorporation

Cold exposure of rats leads to ameliorated glucose and triglyceride utilization with females displaying better adaptation to a cold environment. In the current study, we used hairless rats as a model of increased thermogenesis and analyzed gender-related effects on parameters of lipid and glucose metabolism in the spontaneously hypertensive (SHR) rats. Specifically, we compared hairless coisogenic SHR-Dsg4 males and females harboring mutant Dsg4 (desmoglein 4) gene versus their SHR wild type controls. Two way ANOVA showed significant Dsg4 genotype (hairless or wild type) x gender interaction effects on palmitate oxidation in brown adipose tissue (BAT), glucose incorporation into BAT determined by microPET, and glucose oxidation in skeletal muscles. In addition, we observed significant interaction effects on sensitivity of muscle tissue to insulin action when Dsg4 genotype affected these metabolic traits in males, but had little or no effects in females. Both wild type and hairless females and hairless males showed increased glucose incorporation and palmitate oxidation in BAT and higher tissue insulin sensitivity when compared to wild type males. These findings provide evidence for gender-related differences in metabolic adaptation required for increased thermogenesis. They are consistent with the hypothesis that increased glucose and palmitate utilization in BAT and muscle is associated with higher sensitivity of adipose and muscle tissues to insulin action.

Abstract P452: Evaluation of Pathological Basis of a Shrsp-based Congenic Strain Characterized by Early Stroke Occurrence

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Hiroki Ohara ◽  
Davis L Ngarashi ◽  
Toru Nabika
Keyword(s):  
Congenic Strain ◽  
Spontaneously Hypertensive Rat ◽  
Recent Observation ◽  
Rna Extraction ◽  
Whole Genome Sequence ◽  
Cerebral Stroke ◽  
Spontaneously Hypertensive ◽  
Qrt Pcr ◽  
Wistar Kyoto ◽  
Early Stroke

Objectives: The stroke-prone spontaneously hypertensive rat (SHRSP) is a well-known model for essential hypertension and cerebral stroke. In the previous studies, we have identified a major blood pressure (BP) QTL on chromosome (chr) 1 of SHRSP and have explored gene(s) on the BP QTL responsible for hypertensive phenotypes of this strain through physiological analyses using reciprocal congenic strains between SHRSP and a normotensive control (Wistar-Kyoto rat, WKY). In a recent observation, we unexpectedly found that a SHRSP-based congenic strain, harboring a 0.3-Mbp fragment of the chr1 QTL, has developed stroke earlier than SHRSP. Here, we investigated pathological basis of this congenic strain and attempted to identify gene(s) related to early stroke occurrence. Methods: SHRSP and a SHRSP-based congenic strain SHRSP.WKY-( D1Smu13 )/Izm, abbreviated as SPwch1.71 were used in this study. The rats were housed 12-hour light phase-controlled environment with freely accessible SP diet (Funabashi Farm) and drinking water until at least one suggestive sign of stroke (diminished motor activity, paralytic gait, and so on) was found. MRI by MRmini SA 1508 (DS Pharma Biomedical) was employed to confirm stroke occurrence. BP measurement was performed by the tail-cuff method. Cerebral cortex, brainstem, kidney, adrenal gland and heart obtained from 14 weeks old rats (n=5) were snap-frozen for RNA extraction. Quantitative RT-PCR (qRT-PCR) was performed about 15 of candidate genes located on the chr1 QTL covered by SPwch1.71. Nonsynonymous SNPs were scanned based on the whole-genome sequence of SHRSP and WKY. Results: SPwch1.71 showed significantly high stroke susceptibility compared with SHRSP stroke-free rate until 22 weeks old; SPwch1.71: 0% (0/7), SHRSP: 62.5% (5/8), p <0.001. Systolic BP at 12 weeks old of SPwch1.71 was significantly higher than that of SHRSP (222±4 vs. 206±5, p <0.01, n=5 for each). qRT-PCR identified genes showing modest (<1.5-fold change), but statistically significant different ( p <0.05), in the expression in each tissue examined. Nonsynonymous variations were found in Pde2a , Inppl1 and Folr1 . Pathological significance of expression/sequence variations in the genes remain unclear.

Anatomical and Physiological Aspects of Cardiovascular Function in Wistar—Kyoto and Spontaneously Hypertensive Rats at Birth

1982 ◽  
Vol 63 (s8) ◽  
pp. 383s-385s ◽  
Author(s):  
Sarah D. Gray
Keyword(s):  
Arterial Wall ◽  
Spontaneously Hypertensive Rat ◽  
Left Ventricular ◽  
Small Sample ◽  
Heart Weight ◽  
Spontaneously Hypertensive ◽  
Cell Layers ◽  
The Media ◽  
Wistar Kyoto ◽  
Genetically Determined

1. The present study was designated to determine whether there are any detectable differences in cardiovascular anatomy or physiology between Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR) pups at birth. 2. It was found that mean arterial pressures were significantly higher, heart rates were slightly higher, and heart weight/body weight ratios were higher in SHR. 3. Vascular dimensions were determined in a small sample of those rats, and the data there also indicate hypertrophy to some degree: the ratio of wall thickness/lumen radius was higher in SHR, tangential wall tension and number of cell layers in the media were increased. 4. It is concluded that some of the concomitant features of hypertension, such as left ventricular wall hypertrophy and arterial wall hypertrophy, may be genetically determined to some extent in SHR.

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