Introgressed chromosome 2 quantitative trait loci restores aldosterone regulation and reduces response to salt in the stroke-prone spontaneously hypertensive rat

Sampson, A. K., Mohammed, D., Beattie, W., Graham, D. , Kenyon, C. J., Al-Dujaili, E. A.S., Guryev, V., McBride, M. W. and Dominiczak, A. F. (2014) Introgressed chromosome 2 quantitative trait loci restores aldosterone regulation and reduces response to salt in the stroke-prone spontaneously hypertensive rat. Journal of Hypertension, 32(10), pp. 2013-2021. (doi:10.1097/HJH.0000000000000300)

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Abstract

Background: The genetic contribution to salt-sensitivity in hypertension remains unclear. We have previously identified a quantitative trait locus on chromosome 2 in stroke-prone spontaneously hypertensive rats (SHRSPs) responsible for an increase in SBP in response to a salt challenge. This response is blunted in the congenic SHRSP strain with the Wistar–Kyoto (WKY) chromosome 2 region (10 cM) introgressed (SP.WKYGla2k). We aimed to discover the mechanisms that underlie the effects of this region on salt-handling in the SHRSP strain.<p></p>   Method: Renal and adreno-cortical function were compared in the WKY, SHRSP and the congenic SP.WKYGla2k strains.<p></p>   Results: In response to the salt challenge, all strains excreted more sodium, but the SHRSP strain excreted more protein and a greater amount of sodium compared with either the WKY or the SP.WKYGla2k strain (0.19 ± 0.02 vs. 0.12 ± 0.01 g/24 h and 0.09 ± 0.02 g/24 h, respectively). Glomerular filtration was not affected by diet or genotype, but renal plasma flow was decreased in the SP.WKYGla2k and SHRSP strains. The SHRSP strain had higher plasma aldosterone in association with greater adrenal CYP11B2 (aldosterone synthase) and 3[beta] hydroxysteroid dehydrogenase mRNA gene expression when compared to the WKY strain. Strikingly, introgression of the WKY chromosome 2 region into the SHRSP strain corrected the proteinuria and reduced sodium excretion, plasma aldosterone levels and 3[beta] hydroxysteroid dehydrogenase mRNA gene expression in response to the salt challenge when compared to the SHRSP strain. Glucocorticoid levels and markers of glucocorticoid synthesis were unaffected.<p></p>   Conclusion: Our findings suggest that introgression of the chromosome 2 congenic interval from the WKY into the SHRSP strain is associated with restored aldosterone regulation sufficient to reduce salt-sensitive hypertension and proteinuria.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sampson, Dr Amanda and Graham, Dr Delyth and McBride, Dr Martin and Dominiczak, Professor Anna and Beattie, Mrs Wendy
Authors: Sampson, A. K., Mohammed, D., Beattie, W., Graham, D., Kenyon, C. J., Al-Dujaili, E. A.S., Guryev, V., McBride, M. W., and Dominiczak, A. F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Hypertension
Publisher:Lippincott Williams & Wilkins
ISSN:0263-6352
ISSN (Online):1473-5598

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
2393330BHF ChairAnna DominiczakBritish Heart Foundation (BHF)CH/98001/10285RI CARDIOVASCULAR & MEDICAL SCIENCES
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES
515251EuratransAnna DominiczakEuropean Commission (EC)241504RI CARDIOVASCULAR & MEDICAL SCIENCES