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

Sampson, Amanda K.a; Mohammed, Dashtia; Beattie, Wendya; Graham, Delytha; Kenyon, Christopher J.b; Al-Dujaili, Emad A.S.c; Guryev, Victord; Mcbride, Martin W.a,*; Dominiczak, Anna F.a,*

Journal of Hypertension:
doi: 10.1097/HJH.0000000000000300
ORIGINAL PAPERS: Genetic aspects
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.

Method: Renal and adreno-cortical function were compared in the WKY, SHRSP and the congenic SP.WKYGla2k strains.

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 3β 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 3β 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.

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.

Author Information

aInstitute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow

bEndocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh

cDietetics, Nutrition and Biological Sciences, Queen Margaret University, Edinburgh, Scotland, UK

dEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre, Groningen, the Netherlands

*Martin W. Mcbride and Anna F. Dominiczak are joint senior authors.

Correspondence to Dr Amanda K. Sampson, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC 3004, Australia. Tel: +61 3 8532 1271; fax: +61 3 8532 1100; e-mail: amanda.sampson@bakeridi.edu.au

Abbreviations: ANOVA, analysis of variance; cDNA, complimentary DNA; eRPF, effective renal plasma flow; GFR, glomerular filtration rate; PAH, para-aminohippuric acid; QTL, quantitative trait locus; SHRSP, stroke-prone spontaneously hypertensive rat; SP.WKYGla2k, chromosome 2 congenic rat strain, comprising the stroke-prone spontaneously hypertensive rat background and a small region on chromosome 2 from the Wistar–Kyoto strain; WKY, Wistar–Kyoto normotensive rat

Received 7 November, 2013

Revised 5 June, 2014

Accepted 5 June, 2014

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