Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3

Abstract

Background:We have previously confirmed the importance of rat chromosome 3 (RNO3) genetic loci on blood pressure elevation, pulse pressure (PP) variability and renal pathology during salt challenge in the stroke-prone spontaneously hypertensive (SHRSP) rat. The aims of this study were to generate a panel of RNO3 congenic sub-strains to genetically dissect the implicated loci and identify positional candidate genes by microarray expression profiling and analysis of next-generation sequencing data.Method and results:A panel of congenic sub-strains were generated containing Wistar–Kyoto (WKY)-introgressed segments of varying size on the SHRSP genetic background, focused within the first 50 Mbp of RNO3. Haemodynamic profiling during salt challenge demonstrated significantly reduced systolic blood pressure, diastolic blood pressure and PP variability in SP.WKYGla3a, SP.WKYGla3c, SP.WKYGla3d and SP.WKYGla3e sub-strains. Only SBP and DBP were significantly reduced during salt challenge in SP.WKYGla3b and SP.WKYGla3f sub-strains, whereas SP.WKYGla3g rats did not differ in haemodynamic response to SHRSP. Those sub-strains demonstrating significantly reduced PP variability during salt challenge also demonstrated significantly reduced renal pathology and proteinuria. Microarray expression profiling prioritized two candidate genes for blood pressure regulation (Dnm1, Tor1b), localized within the common congenic interval shared by SP.WKYGla3d and SP.WKYGla3f strains, and one candidate gene for salt-induced PP variability and renal pathology (Rabgap1), located within the region unique to the SP.WKYGla3d strain. Comparison of next-generation sequencing data identified variants within additional positional genes that are likely to affect protein function.Conclusion:This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge.

Integrative genomic analysis of blood pressure and related phenotypes in rats

“…Based on the results of current linkage analysis in a Japanese colony and previous congenic mapping in other colonies involving SHR, SHRSP and WKY ( Frantz et al, 1998 ; Hübner et al, 1999 ; Alemayehu et al, 2002 ; McBride et al, 2003 ; Monti et al, 2003 ; Koh-Tan et al, 2017 ), we constructed consomic strains for a total of nine chromosomes by using simple sequence length polymorphism markers ( ): i.e. RNO1, RNO3, RNO4 and RNO15 for both SHR/Izm and SHRSP/Izm; RNO2 and RNO19 for SHR/Izm; and RNO7, RNO8, RNO9 and RNO13 for SHRSP/Izm to be used as a recipient strain ( Fig.…”

Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats

“…4B and table S2). Blood pressures were monitored weekly and increased in all rats over time (as expected as they mature to adulthood) (35) but were clustered into two groups: one with high blood pressure (untreated DM rats and rats treated with simvastatin or cilostazol) and the other with normal blood pressure (DM rats treated with the antihypertensives perindopril or H+H and untreated WKY rats; Fig. 4C).…”

A unified mapping framework of multifaceted pharmacodynamic responses to hypertension interventions

“…Increasing evidence from large-scale epidemiological cohort studies has shown that the difference of SBP from DBP, defined as PP reflecting arterial stiffness, and two thirds of DBP plus one third of SBP, defined as MAP reflecting left ventricular contractility and heart rate, are highly associated with heart function, disease, and aging [7][8][9][10]15 . Genetic studies have demonstrated the genetic variation of PP and MAP [12][13][14] , suggesting that the influences of these two BP traits on heart dysfunction may vary inter-individually. As such, it is essential to investigate the genetic basis of these BP-parameters responses to drug interventions, which should be based on personalized medicine, to best prevent and treat cardiovascular disease, thereby improving quality of life and prolonging life expectancy.…”

“…Previous studies through genetic mapping and genome-wide association mapping have identified important quantitative trait loci (QTLs) that affect MAP and PP in animal and human populations [12][13][14][15] . In a meta-analysis of 150,134 individuals from 54 genome-wide association studies of European ancestry with 1000 Genomes Project-based imputation, Wain et al 16 identified a total of 48 genes that are involved in differences of SBP, DBP and PP among humans.…”