Variants in striatin gene are associated with salt-sensitive blood pressure in mice and humans.
Variants in striatin gene are associated with salt-sensitive blood pressure in mice and humans.
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DOI：
10.1161/hypertensionaha.114.04233
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发表时间：
2015-01
期刊：
影响因子：
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通讯作者：
Williams GH
中科院分区：
文献类型：
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作者：
Garza AE;Rariy CM;Sun B;Williams J;Lasky-Su J;Baudrand R;Yao T;Moize B;Hafiz WM;Romero JR;Adler GK;Ferri C;Hopkins PN;Pojoga LH;Williams GH
纹状蛋白是一种新型蛋白，可与类固醇受体相互作用，并在体外快速改变非基因组活性。我们在动物模型中测试了纹状蛋白反过来影响矿皮质激素受体功能从而影响钠、水和血压稳态的假设。我们评估了新型纹状蛋白杂合子敲除小鼠血压的盐敏感性。与野生型相比，当钠摄入量从限制型（0.03%）增加到自由型（1.6%）时，纹状蛋白杂合子的血压显著升高。此外，与野生型小鼠相比，纹状蛋白杂合子小鼠的肾脏中矿糖皮质激素受体及其基因组下游靶点血清/糖皮质激素调节激酶1和上皮钠通道的表达增加，而矿糖皮质激素受体快速非基因组途径的pAkt/Akt比率降低。为了确定这些发现的潜在临床相关性，我们测试了366名高加索高血压患者纹状蛋白基因单核苷酸多态性变异与血压盐敏感性之间的关系。HapMap衍生的标记单核苷酸多态性鉴定出rs2540923与血压盐敏感性之间的关联（OR, 6.25; 95% CI 1.7-20； P=0.01）。这些数据为人类和啮齿类动物提供了第一个将纹状蛋白与矿物皮质激素受体活性标志物联系起来的活体证据。这些数据也支持了一个假设，即快速的、非基因组的矿化皮质激素受体途径（通过纹状蛋白介导）在调节盐摄入量和血压之间的相互作用中起作用。
Striatin is a novel protein that interacts with steroid receptors and modifies rapid, non-genomic 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. When 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). Further, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocoticoid-regulated kinase 1 and epithelial sodium channel were increased in striatin heterozygote versus wild type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocoriticoid receptor's rapid, non-genomic 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 presure in 366 Caucasian hypertensive subjects. HapMap derived tagging single nucleotide polymorphisms identified an association between rs2540923 with salt sensitivity of blood pressure (OR, 6.25; 95% CI 1.7-20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocoriticoid receptor activity. The data also support the hypothesis that the rapid, non-genomic mineralocoriticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure.