Kidney Specificity of Rat Chromosome 1 Blood Pressure Quantitative Trait Locus Region

Abstract

Abstract-Rat chromosome 1 has a region containing loci that influence blood pressure. In the present study, we investigated whether these loci mediate their effect via the kidney. Taking advantage of the histocompatability between a congenic strain (WKY.SHR-Sa, which contains the relevant chromosomal region from the spontaneously hypertensive rat) and its parental strain, the Wistar-Kyoto rat (WKY), we compared the effect of transplanting a kidney at 5 to 6 weeks of age from either congenic rats or WKY into bilaterally nephrectomized WKY. WKY.SHR-Sa animals and WKY with intact kidneys and with unilateral nephrectomy were studied as controls. Blood pressure was measured at 12, 16, 20, and 25 weeks of age. At all time points, blood pressure was significantly higher (by between 8 to 22 mm Hg, PϽ0.001) in 2-kidney WKY.SHR-Sa animals compared with WKY. This genotype-related difference was maintained in unilaterally nephrectomized rats. Most importantly, WKY that received transplants from WKY.SHR-Sa rats had significantly higher blood pressure (PϽ0.001 at all time points) compared with those that received transplants from other WKY. At any age, this difference was between 70% to 100% of the difference observed between the 1-kidney groups. There was no difference in plasma urea or creatinine between groups or evidence of chronic rejection in the cross-transplant group.The findings indicate that the major proportion of the blood pressure effect of loci on rat chromosome 1 is mediated through the kidney, and provide a rational basis for investigating genes located in the relevant chromosomal region and expressed in the kidney as likely candidates. Key Words: hypertension, experimental Ⅲ genetics Ⅲ rats, spontaneously hypertensive Ⅲ genes Ⅲ transplantation, renal I n the past decade, quantitative trait loci (QTLs) affecting blood pressure (BP) have been mapped to regions on several rat chromosomes by use of linkage analysis in segregating progeny from crosses of inbred hypertensive and normotensive rat strains. 1 In many instances, the presence of the QTLs has been confirmed by their capture in congenic strains. 1 These are strains in which a chromosomal region from one strain (eg, a hypertensive strain) is introgressed into another (eg, normotensive) strain by marker-selected backcrossing. 2 If the QTL is present in the introgressed segment, the congenic strain should have a different BP (higher in the above example) than that of the recipient parental strain.In previous studies, we 3 and others 1 have shown that a region in the midportion of rat chromosome 1 (RNO1) has Ն1 QTLs affecting BP. In second filial generation (F 2 ) progeny from a cross of the spontaneously hypertensive rat (SHR) and the Wistar-Kyoto rat (WKY) strains, the QTL region accounted for Ϸ25% of the variance in BP. 3 This segment of RNO1 is particularly interesting because it also harbors QTLs for stroke latency, 4 renal damage, 5 and diabetes-related phenotypes. 6 More recently, we have captured the region containing the BP QTL(s) in reciprocal conge...

Closely linked non-additive blood pressure quantitative trait loci

“…Multiple-strain comparisons have identified QTLs on this chromosome (Clemitson et al 2002(Clemitson et al , 2007Cui et al 2003Cui et al , 2004Frantz et al 1998Frantz et al , 2001Hubner et al 1999;Iwai et al 1998;Joe et al 2003;Kato et al 2003;Kloting et al 1998;Monti et al 2003;Saad et al 1999Saad et al , 2001St Lezin et al 1999;Yagil et al 2003;Yao et al 2007). Of the three RNO1 BP QTLs reported from our laboratory (Saad et al 2001), the present study focused on QTL1b.…”

The Kidney as a Determinant of Genetic Hypertension

“…22 Later attempts to narrow down a specific segment of the genome that may be responsible for the phenomenon that blood pressure often follows the kidney in renal transplantation studies were more successful. 8,9 One study 8 used a congenic SHR (CSHR) strain that harbors a 22-cM segment of chromosome 1 from the normotensive Brown-Norway rat (BN). Systolic blood pressure was Ϸ20 mm Hg lower in CSHR than in the progenitor SHR strain.…”

“…Another recent study 9 used congenic WKY (ConWKY) harboring a segment of chromosome 1 from SHR. Systolic blood pressure was Ϸ20 mm Hg higher in ConWKY than in the progenitor WKY strain.…”

“…The increment in blood pressure in ConWKY versus WKY was largely transmitted with a ConWKY kidney graft to WKY recipients, indicating that the major portion of the blood pressure effect of loci on rat chromosome 1 is mediated through the kidney. The 2 studies using chromosome 1 congenic rats 8,9 are at variance with each other with respect to the kidney-mediated blood pressure effects of loci on chromosome 1. Whereas one study 8 found that the kidney-specific transfer of a DNA segment from SHR had no effect on blood pressure in the recipients, the other study 9 found an increase in blood pressure.…”

“…The 2 studies using chromosome 1 congenic rats 8,9 are at variance with each other with respect to the kidney-mediated blood pressure effects of loci on chromosome 1. Whereas one study 8 found that the kidney-specific transfer of a DNA segment from SHR had no effect on blood pressure in the recipients, the other study 9 found an increase in blood pressure. The reasons for this discrepancy are unclear.…”