A novel-1364A/C aquaporin 5 gene promoter polymorphism influences the responses to salt loading of the renin-angiotensin-aldosterone system and of blood pressure in young healthy men
A novel-1364A/C aquaporin 5 gene promoter polymorphism influences the responses to salt loading of the renin-angiotensin-aldosterone system and of blood pressure in young healthy men
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DOI：
10.1007/s00395-008-0750-z
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发表时间：
2008-11-01
影响因子：
9.5
通讯作者：
Siffert, Winfried
中科院分区：
文献类型：
--
作者：
Adamzik, Michael;Frey, Ulrich H.;Siffert, Winfried
背景水通道蛋白水通道家族有助于水和盐的稳态。 AQP5 是一种普遍表达的外分泌型水通道。 AQP5 中改变基因转录的功能性单核苷酸多态性尚未被描述。因此，我们对人 AQP5 启动子进行了测序，以检测可能影响 AQP5 表达并导致肾素-血管紧张素-醛固酮系统 (RAAS) 表型变异的新序列变异。方法和结果 整个 AQP5 启动子的测序揭示了一种新的 1364A/C 多态性。通过电泳迁移率变动测定测试，用 C 替代 A 与转录因子结合增加相关，但 cAMP 和血清对 AQP5 基因的转录激活显着降低。 C 等位基因与人类心脏中 mRNA 的显着降低以及红细胞膜中蛋白质表达的降低有关。最后，我们将 AQP5 基因型与两个独立研究队列中 RAAS 的变异性相关联。首先，我们研究了 103 名年轻（26 +/- 3 岁）健康男性在膳食盐摄入量增加的情况下 RAAS 的表型变异。在 AC/CC 基因型中，增加盐摄入量使血浆血管紧张素 II 降低 25%，但在 AA 基因型中仅降低 2%（P = 0.012）；在 AC/CC 基因型受试者中，血清醛固酮降低 34%，但在 AA 基因型中仅降低 19%（P = 0.005）。两种基因型在盐饮食下血压均升高（P < 0.01），这在 AA 基因型中更为明显（P = 0.029）。其次，我们研究了 96 名患有冠状动脉疾病、计划进行冠状动脉旁路移植术的老年患者（68 +/- 10 岁）的 RAAS 变量的相关性。 AA 基因型的醛固酮血清浓度是 AC/CC 基因型的 2 倍（P < 0.001），血管紧张素 II 血浆浓度是 AC/CC 基因型的 4 倍，而 ADH 血浆浓度没有差异。结论 AQP5 基因启动子中的一个新的单核苷酸多态性改变了不同体外系统和细胞中的 AQP5 表达，并且与年轻健康男性和冠状动脉疾病患者中 RAAS 变量的改变相关。
Background The family of aquaporin water channels contributes to water and salt homeostasis. AQP5 is a ubiquitously expressed exocrine-type water channel. Functional single nucleotide polymorphisms in AQP5 which alter gene transcription have not yet been described. We, therefore, sequenced the human AQP5 promoter to detect novel sequence variants which could impact upon AQP5 expression and contribute to the phenotypic variability of the renin-angiotensin-aldosterone system (RAAS). Methods and results Sequencing of the whole AQP5 promoter revealed a novel-1364A/C polymorphism. Substitution of C for A was associated with increased transcription factor binding as tested by electrophoretic mobility shift assay, but significantly reduced transcriptional activation of the AQP5 gene by cAMP and serum. The C allele was associated with significantly decreased mRNA in human heart and with decreased protein expression in erythrocyte membranes. Finally, we associated AQP5 genotypes with the variability of the RAAS in two independent study cohorts. First, we studied the phenotypic variability of the RAAS in 103 young (26 +/- 3 years) healthy males under an increased dietary salt intake. Increasing salt intake decreased plasma angiotensin II by 25% in AC/CC genotypes but only by 2% in AA genotypes (P = 0.012), and it decreased serum aldosterone by 34% in subjects with AC/CC genotypes but only by 19% in the AA genotypes (P = 0.005). Both genotypes had increased blood pressure under salt diet (P < 0.01), which was significantly more pronounced in AA genotypes (P = 0.029). Second, we investigated associations with variables of the RAAS in 96 old patients (68 +/- 10 years) with coronary artery disease scheduled for coronary artery bypass grafting. Aldosterone serum concentrations were 2-fold (P < 0.001) and angiotensin II plasma concentrations were 4-fold higher in AA genotypes than in AC/CC genotypes while ADH plasma concentrations did not differ. Conclusion A novel single nucleotide polymorphism in the AQP5 gene promoter alters AQP5 expression in different in vitro systems and cells, and is associated with alterations of variables of the RAAS both in young healthy males and in patients with coronary artery disease.