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Hypertension. 2014 Oct;64(4):883-90. doi: 10.1161/HYPERTENSIONAHA.114.03550. Epub 2014 Jul 7.

Refined mapping of a hypertension susceptibility locus on rat chromosome 12.

Author information

1
From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
2
From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee. jlazar@mcw.edu.

Abstract

Previously, we found that transferring 6.1 Mb of salt-sensitive (SS) chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12(BN) background significantly elevated mean arterial pressure in response to an 8% NaCl diet (178±7 versus 144±2 mm Hg; P<0.001). Using congenic mapping, we have now narrowed the blood pressure locus by 86% from a 6.1-Mb region containing 133 genes to an 830-kb region (chr12:14.36-15.19 Mb) with 14 genes. Compared with the SS-12(BN) consomic, the 830-kb blood pressure locus was associated with a ∆+15 mm Hg (P<0.01) increase in blood pressure, which coincided with elevated albuminuria (∆+32 mg/d; P<0.001), proteinuria (∆+48 mg/d; P<0.01), protein casting (∆+154%; P<0.05), and renal fibrosis (∆+79%; P<0.05). Of the 14 genes residing in the 830-kb locus, 8 were differentially expressed, and among these, Chst12 (carbohydrate chondroitin 4 sulfotransferase 12) was most consistently downregulated by 2.6- to 4.5-fold (P<0.05) in both the renal medulla and cortex under normotensive and hypertensive conditions. Moreover, whole genome sequence analysis of overlapping blood pressure loci revealed an ≈86-kb region (chr12:14 541 567-14 627 442 bp) containing single-nucleotide variants near Chst12 that are unique to the hypertensive SS strain when compared with the normotensive Brown Norway, Dahl salt-resistant, and Wistar-Kyoto strains. Finally, the 830-kb interval is syntenic to a region on human chromosome 7 that has been genetically linked to blood pressure, suggesting that insight gained from our SS-12(BN) congenic strain may be translated to a better understanding of human hypertension.

KEYWORDS:

hypertension; rats, inbred BN; rats, inbred Dahl

PMID:
25001272
PMCID:
PMC4162822
DOI:
10.1161/HYPERTENSIONAHA.114.03550
[Indexed for MEDLINE]
Free PMC Article

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