Variants in striatin gene are associated with salt-sensitive blood pressure in mice and humans

Abstract

Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor's rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7-20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure.

Keywords: blood pressure; polymorphism, single nucleotide; striatin protein, mouse.

© 2014 American Heart Association, Inc.

Figures

Figure 1

Aldosterone rapid non-genomic actions in EA.hy926 cells. A) EA.hy926 cells treated acutely with 50 nM ALDO. B.) Cells transfected with 1 nM striatin siRNA or scramble siRNA were stimulated with ALDO for 15 minutes. pAkt/Akt levels were assessed by Western blot. Data represent means ± SEM (n=4 in duplicate).

Figure 2

Strn gene targeting in mice. Western blot analysis of striatin expression in adrenal, heart and kidney tissue. Gels for striatin and β-actin are presented for each tissue/genotype. Data represent mean ± SD, N=4. *p<0.01, comparing WT to Strn+/− mice.

Figure 3

Change in systolic blood pressure in response to changes in sodium intake. Delta is calculated as systolic BP on 1.6% Na+ minus systolic BP on 0.03% Na+ diet. Data represent means ± SEM (n=13 per genotype). P value for student t-test comparing WT and Strn+/−.

Figure 4

Effect of dietary Na+ on ALDO production in vivo and ex vivo in WT and Strn+/− mice. PRA levels on (A) ResS or (B) LibS diets (n=4-8/group). Plasma ALDO levels on a (C) ResS or (D) LibS diets (n=4-8/group). ALDO production is assessed in media from isolated zona glomerulosa cells (ZG) ZG in the presence or absence of ANGII 10−7 M for 2 hours on (E) ResS and (F) LibS diets. ALDO. Black bar indicates WT, open bar indicates Strn+/−. Data expressed as mean ± SEM; * indicates p<0.001.

Figure 5

Molecular studies using heart and kidney tissue. pAkt/Akt ratio protein expression in heart (A) and kidney (B). mRNA expression using real-time PCR in kidney cortical tissue: MR (C), SGK1 (D) and ENaC (E). * p

Figure 6

SNP and SS of BP associations in a hypertensive population. Data represent mean ± SD.