Single-Nucleotide Polymorphisms (SNPs) Both Associated with Hypertension and Contributing to Accelerated-Senescence Traits in OXYS Rats

Abstract

Aging is a major risk factor of numerous human diseases. Adverse genetic variants may contribute to multiple manifestations of aging and increase the number of comorbid conditions. There is evidence of links between hypertension and age-related diseases, although the genetic relationships are insufficiently studied. Here, we investigated the contribution of hypertension to the development of accelerated-senescence syndrome in OXYS rats. We compared transcriptome sequences of the prefrontal cortex, hippocampus, and retina of OXYS rats with the genotypes of 45 rat strains and substrains (which include models with hypertension) to find single-nucleotide polymorphisms (SNPs) both associated with hypertension and possibly contributing to the development of age-related diseases. A total of 725 polymorphisms were common between OXYS rats and one or more hypertensive rat strains/substrains being analyzed. Multidimensional scaling detected significant similarities between OXYS and ISIAH rat genotypes and significant differences between these strains and the other hypertensive rat strains/substrains. Nonetheless, similar sets of SNPs produce a different phenotype in OXYS and ISIAH rats depending on hypertension severity. We identified 13 SNPs causing nonsynonymous amino-acid substitutions having a deleterious effect on the structure or function of the corresponding proteins and four SNPs leading to functionally significant structural rearrangements of transcripts in OXYS rats. Among them, SNPs in genes Ephx1, Pla2r1, and Ccdc28b were identified as candidates responsible for the concomitant manifestation of hypertension and signs of accelerated aging in OXYS rats.

Animal Models of Hypertension (ISIAH Rats), Catatonia (GC Rats), and Audiogenic Epilepsy (PM Rats) Developed by Breeding

“…The estimation of the distances (by multivariate scaling) between the genotypes of hypertensive ISIAH/Icgn rats and the 11 hypertensive strains and sub-strains of the rats listed above has uncovered significant differences in the ISIAH genotype from the genotypes of all analyzed strains [21]. On the other hand, the genotype of ISIAH rats turned out to be quite similar to that of the OXYS [59] rat strain, which was also selected at the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences (ICG SB RAS) from the same outbred stock of Wistar rats as the ISIAH rats. The selection of OXYS rats was based on a trait that was not related to BP; nevertheless, OXYS rats have moderately elevated BP [60].…”

Stress Reactivity, Susceptibility to Hypertension, and Differential Expression of Genes in Hypertensive Compared to Normotensive Patients

“…On this basis, we sequenced transcriptomes in the brain stem [ 43 ], hypothalamus [ 44 ], renal medulla [ 45 ], renal cortex [ 46 ], and adrenal glands [ 47 ] of hypertensive ISIAH rats versus normotensive WAG rats. Besides this, we profiled transcriptomes of the hippocampus [ 40 ], prefrontal cortex [ 41 ], and retina [ 42 ] in OXYS rats (ICG SB RAS, Novosibirsk, Russia), which spontaneously develop the accelerated-senescence phenotype against a background of moderately high blood pressure [ 65 , 66 , 67 , 68 ] with respect to normotensive Wistar rats. In the present work, we meta-analyzed our eight abovementioned RNA-Seq datasets to ensure out of caution that among them (together with those available in PubMed [ 69 ]), there are still no invariant molecular markers of hypertension.…”

Calorie Restriction Provides Kidney Ischemic Tolerance in Senescence-Accelerated OXYS Rats

“…The OXYS strain was derived from the Wistar rats via selection for susceptibility to cataractogenic effects of a galactose-rich diet as described earlier [ 16 ]. Then, it has been discovered that OXYS rats spontaneously develop accelerated-senescence syndrome, as early manifestation of a phenotype similar to human geriatric disorders including cataract, involution of the thymus, hypertrophic cardiomyopathy, sarcopenia, osteoporosis, AMD-like retinopathy, and signs of Alzheimer’s disease [ 17 , 18 , 19 , 20 , 21 , 22 ]. Phenotypic manifestations of all these pathologies occur at the age of 3 months and then gradually accelerate.…”