Increased NBCn1 expression, Na⁺/HCO^- ₃ co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

TY - JOUR

T1 - Increased NBCn1 expression, Na+/HCO- 3 co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

AU - Ng, Fu Liang

AU - Boedtkjer, Ebbe

AU - Witkowska, Kate

AU - Ren, Meixia

AU - Zhang, Ruoxin

AU - Tucker, Arthur

AU - Aalkjær, Christian

AU - Caulfield, Mark J.

AU - Ye, Shu

PY - 2017

Y1 - 2017

N2 - Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO- 3 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 pHi 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.

AB - Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO- 3 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 pHi 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.

U2 - 10.1093/hmg/ddx015

DO - 10.1093/hmg/ddx015

M3 - Journal article

C2 - 28087731

AN - SCOPUS:85019072808

SN - 0964-6906

VL - 26

SP - 989

EP - 1002

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 5

M1 - ddx015

ER -