Genetically Hypertensive Brown Norway Congenic Rat Strains Suggest Intermediate Traits Underlying Genetic Hypertension

Abstract

Aim To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background.Methods Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry in the single and combined congenics. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics.Results Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (β = -1.25 ± 0.17), whereas BN.GH2 (β = 0.66 ± 0.09) and BN.GH18 (β = 0.71 ± 0.07) had significantly decreased responses to ANGII from those observed in the BN (β = 0.88 ± 0.08). ConclusionThe failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome backgrounddependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.

Implication of chromosome 13 on hypertension and associated disorders in Lyon hypertensive rats

“…This is not a new concept by any means, even when generating consomics and congenics from the same strains as used in mapping crosses. For example, in one study we recently published [33], introgression of all three major BP QTL alleles from the Genetically Hypertensive (GH) rat, independently or in a triple congenic, onto the background of the BN rat was not sufficient to significantly raise blood pressure. Conversely, consomics are very useful for identifying additional loci in the absence of genome background effects.…”

Opportunities and limitations of genetic analysis of hypertensive rat strains

“…Gilibert et al . [42] also recognize that the present and a previous study both demonstrate the presence of powerful homeostatic mechanisms preventing the development of hypertension in the Brown Norway strain [52]. The presence of protective loci in chromosome 13 of the Brown Norway rat against the development of hypertension has been known for several years [7,58,59].…”

“…Generation of congenic strains has been successfully utilized by several groups by introgressing target chromosomal regions from the hypertension-resistant Brown Norway strain onto the SHR genome [51] or from regions of several genetically hypertensive rat chromosomes onto the Brown Norway background [52]. The Lyon investigators have recently constructed reciprocal consomic strains, a variation of congenic strains in which a whole chromosome rather than a chromosomal region is back-crossed [53].…”

Chrm3 Gene and M3 Muscarinic Receptors Contribute to Salt-Sensitive Hypertension

“…From a broader perspective, the goal is to determine the functional relevance of any novel gene found to be involved in hypertension in humans or rodents. Although the importance of genomic context is unquestionable 5 , correlated orthologous rat-human phenotype-genotype associations are common 6–8 and although negative associations are not helpful, positive associations are likely to improve our understanding of human risk. At this point in time, the availability and application of gene editing techniques using Crisper-Cas9 in rodents provides remarkable opportunities not previously available to study the functional pathways and consequences of hypertension associated candidate genes found in rodents and human GWAS studies.…”