Targeted mutation of SLC4A5 induces arterial hypertension and renal metabolic acidosis
Targeted mutation of SLC4A5 induces arterial hypertension and renal metabolic acidosis
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DOI：
10.1093/hmg/ddr533
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发表时间：
2012-03-01
影响因子：
3.5
通讯作者：
Boettger, Thomas
中科院分区：
文献类型：
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作者：
Groeger, Nicole;Vitzthum, Helga;Boettger, Thomas
基于单核苷酸多态性与血压（BP）水平和高血压状态的关联，人SLC 4A 5基因已被鉴定为高血压易感基因。这种关联的生化基础尚不清楚，特别是因为没有单一的基因变异与人类高血压有关。SLC 4A 5（NBCe 2，NBC 4）在肾脏的集合管中表达，并作为一种产电离子转运蛋白，以1：2或1：3的化学计量转运钠和碳酸氢盐，允许碳酸氢盐重吸收，同时吸收相对较少的钠。我们在小鼠中突变了Slc 4a 5基因，导致收缩压和舒张压持续升高。Slc 4a 5突变小鼠也表现出代偿性代谢性酸中毒和低血凝素性低醛固酮症。肾脏生理学分析显示液体摄入量和尿液排泄量增加，肾小球滤过率增加。转录组分析揭示了SLC 4A 5突变诱导的可能代偿机制，包括SLC 4A 7和pendrin的上调以及与高血压相关的分子机制。诱导代谢紊乱消除了野生型和Slc 4a 5突变小鼠之间的血压差异。我们的结论是SLC 4A 5功能的损害有利于高血压状态的发展。我们的理由是，SLC 4A 5的钠保留碳酸氢盐重吸收的损失启动了一个调节级联，包括通过其他钠-碳酸氢盐转运蛋白（例如SLC 4A 7）的补偿性碳酸氢盐重吸收，代价是钠摄取增加。这将最终升高血压并导致醛固酮减少症，从而为SLC 4A 5基因座与人类高血压的联系提供了一种机制解释。
The human SLC4A5 gene has been identified as a hypertension susceptibility gene based on the association of single nucleotide polymorphisms with blood pressure (BP) levels and hypertension status. The biochemical basis of this association is unknown particularly since no single gene variant was linked to hypertension in humans. SLC4A5 (NBCe2, NBC4) is expressed in the collecting duct of the kidney and acts as an electrogenic ion-transporter that transports sodium and bicarbonate with a 1:2 or 1:3 stoichiometry allowing bicarbonate reabsorption with relatively minor concurrent sodium uptake. We have mutated the Slc4a5 gene in mice, which caused a persistent increase in systolic and diastolic BP. Slc4a5 mutant mice also displayed a compensated metabolic acidosis and hyporeninemic hypoaldosteronism. Analysis of kidney physiology revealed elevated fluid intake and urine excretion and increased glomerular filtration rate. Transcriptome analysis uncovers possible compensatory mechanisms induced by SLC4A5 mutation, including upregulation of SLC4A7 and pendrin as well as molecular mechanisms associated with hypertension. Induction of metabolic alkalosis eliminated the BP difference between wild-type and Slc4a5 mutant mice. We conclude that the impairment of the function of SLC4A5 favors development of a hypertensive state. We reason that the loss of sodium-sparing bicarbonate reabsorption by SLC4A5 initiates a regulatory cascade consisting of compensatory bicarbonate reabsorption via other sodium-bicarbonate transporters (e.g. SLC4A7) at the expense of an increased sodium uptake. This will ultimately raise BP and cause hypoaldosteronism, thus providing a mechanistic explanation for the linkage of the SLC4A5 locus to hypertension in humans.