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Increased NBCn1 expression, Na+/HCO3- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension.

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posted on 17.01.2017, 11:40 by F. Liang Ng, E. Boedtkjer, K. Witkowska, M. Ren, R. Zhang, A. Tucker, C. Aalkjær, M. J. Caulfield, Shu Ye
Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na(+)/HCO3 co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na(+)/H(+) exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pH i regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure.

Funding

Fu Liang Ng is a recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/12/82/29736). This work also falls under the portfolio of research conducted within the National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, and the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit supported and funded by the National Institute of Health Research.

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Citation

Human Molecular Genetics, 2017, 26 (5), pp. 989–1002

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

Human Molecular Genetics

Publisher

Oxford University Press (OUP)

issn

0964-6906

eissn

1460-2083

Acceptance date

20/12/2016

Copyright date

2017

Available date

17/01/2017

Publisher version

https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddx015

Language

en

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