Candidate genes that determine response to salt in the stroke-prone spontaneously hypertensive rat - Congenic analysis

Graham, D. et al. (2007) Candidate genes that determine response to salt in the stroke-prone spontaneously hypertensive rat - Congenic analysis. Hypertension, 50(6), pp. 1134-1141. (doi:10.1161/HYPERTENSIONAHA.107.095349)

Graham, D. et al. (2007) Candidate genes that determine response to salt in the stroke-prone spontaneously hypertensive rat - Congenic analysis. Hypertension, 50(6), pp. 1134-1141. (doi:10.1161/HYPERTENSIONAHA.107.095349)

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Abstract

The existence of blood pressure quantitative trait loci exaggerated by salt on rat chromosome 2 has been confirmed previously using congenic strains derived from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. This study aimed to dissect the implicated chromosome 2 region and to identify candidate genes based on microarray expression profiling and real-time PCR. A marker-assisted breeding strategy generated congenic strains SP.WKYGla2a (D2Rat13-D2Rat157), SP.WKYGla2c* (D2Wox9-D2Mgh12), and SP.WKYGla2k (D2Mit21-D2Rat157) using SHRSP as the recipient and WKY as the donor strain. The SP.WKYGla2k strain contains a 10-cM congenic interval, which is encompassed within the larger (64-cM) SP.WKYGla2a congenic region. Salt-loaded systolic blood pressure, measured by radiotelemetry, was significantly lower in the SP.WKYGla2a and SP.WKYGla2k strains compared with SHRSP. Salt sensitivity in SP.WKYGla2c* was not significantly different from SHRSP. Exclusion mapping identified a 6-Mbp region harboring genes responsible for salt-sensitive blood pressure regulation. Microarray expression profiling was carried out in whole homogenized kidneys from parental and SP.WKYGla2a strains. Examination of expression data within the minimal congenic interval identified the positional candidates Edg1 and Vcam1, demonstrating significantly elevated renal RNA expression levels in the SHRSP compared with WKY and SP.WKYGla2a congenic strains. These results were confirmed by quantitative real-time PCR. DNA sequencing identified SNPs in both Edg1 and Vcam1 between SHRSP and WKY rats. In conclusion, we have identified a suggestive minimal interval encompassing a 6-Mbp region on rat chromosome 2. This region contains several physiological candidate genes for salt-sensitive hypertension in the SHRSP, including Edg1 and Vcam1, which are differentially expressed and lie on common and functionally important pathways.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Miller, Dr William and McBride, Dr Martin and Dominiczak, Professor Anna and Beattie, Mrs Elisabeth and McClure, Dr John and Graham, Dr Delyth and Touyz, Professor Rhian and Gaasenbeek, Dr Michelle
Authors: Graham, D., McBride, M.W., Gaasenbeek, M., Gilday, K., Beattie, E., Miller, W.H., McClure, J.D., Polke, J.M., Montezano, A., Touyz, R.M., and Dominiczak, A.F.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
239331BHF ChairAnna DominiczakBritish Heart Foundation (BHF)CH/98001Institute of Cardiovascular and Medical Sciences
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633Institute of Cardiovascular and Medical Sciences
387461Functional characteristics of the Gstm1 deficiency in the stroke prone spontaneously hypertensive rat - in vitro and in vivo studiesAnna DominiczakBritish Heart Foundation (BHF)PG/04/101/17652Institute of Cardiovascular and Medical Sciences
302341Cardiovascular Functional genomics - Translating experimental work to human diseaseAnna DominiczakWellcome Trust (WELLCOME)066780/Z/01/ZInstitute of Cardiovascular and Medical Sciences