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

Amanda K. Sampson*, Dashti Mohammed, Wendy Beattie, Delyth Graham, Christopher J. Kenyon, Emad A. S. Al-Dujaili, Victor Guryev, Martin W. Mcbride, Anna F. Dominiczak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.WKY(Gla)2k). 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.WKY(Gla)2k 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.WKY(Gla)2k 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.WKY(Gla)2k 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.

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.

Original languageEnglish
Pages (from-to)2013-2021
Number of pages9
JournalJournal of Hypertension
Volume32
Issue number10
DOIs
Publication statusPublished - Oct 2014

Keywords

  • aldosterone
  • cardiovascular disease - salt intake
  • gene expression/regulation
  • genetics - animal models
  • ENDOTHELIAL NITRIC-OXIDE
  • GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM
  • BLOOD-PRESSURE
  • 3-BETA-HYDROXYSTEROID DEHYDROGENASE
  • CARDIAC-HYPERTROPHY
  • GENETIC-HYPERTENSION
  • MOLECULAR MECHANISMS
  • SEX-DIFFERENCES
  • SENSITIVE RAT
  • DIETARY SALT

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