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首页> 外文期刊>Molecular and Cellular Biology >Hypertension and Impaired Glycine Handling in Mice Lacking the Orphan Transporter XT2
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Hypertension and Impaired Glycine Handling in Mice Lacking the Orphan Transporter XT2

机译：缺乏孤儿转运蛋白XT2的小鼠高血压和甘氨酸处理受损。

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A family of orphan transporters has been discovered that are structurally related to the Na+-Cl?-dependent neurotransmitter transporters, including the dopamine transporter. One member of this family, the mouse XT2 gene, is predominantly expressed in the kidney and has 95% homology to rat ROSIT (renal osmotic stress-induced Na+-Cl? organic solute cotransporter). To study the physiological functions of this transporter, we generated XT2-knockout mice by gene targeting. XT2?/? mice develop and survive normally with no apparent abnormalities. To attempt to identify potential substrates for XT2, we screened urine from XT2-knockout mice by high-pressure liquid chromatography and mass spectrometry and found significantly elevated concentrations of glycine. To study glycine handling, XT2+/+ and XT2?/? mice were injected with radiolabeled glycine, and urine samples were collected to monitor glycine excretion. After 2 h, XT2?/? mice were found to excrete almost twice as much glycine as the XT2+/+ controls (P = 0.03). To determine whether the absence of the XT2 transporter affected sodium and fluid homeostasis, we measured systolic blood pressure by computerized tail-cuff manometry. Systolic blood pressure was significantly higher in XT2?/? mice (127 ± 3 mmHg) than in wild-type controls (114 ± 2 mmHg; P < 0.001). This difference in systolic blood pressure was maintained on high and low salt feeding. To examine whether the alteration in blood pressure and the defect in glycine handling were related, we measured systolic blood pressure in the XT2?/? mice during dietary glycine supplementation. Glycine loading caused systolic blood pressure to fall in the XT2?/? mice from 127 ± 3 to 115 ± 3 mmHg (P < 0.001), a level virtually identical to that of the wild-type controls. These data suggest that the XT2 orphan transporter is involved in glycine reabsorption and that the absence of this transporter is sufficient to cause hypertension.
机译：已经发现了一个与Na + -Cl ？依赖的神经递质转运蛋白在结构上相关的孤儿转运蛋白家族，包括多巴胺转运蛋白。该家族的一个成员，即小鼠XT2基因，主要在肾脏中表达，与大鼠ROSIT具有95％的同源性（肾渗透压诱导的Na + -Cl ？有机溶质共转运蛋白）。为了研究这种转运蛋白的生理功能，我们通过基因靶向产生了XT2基因敲除小鼠。 XT2 ？/？小鼠正常发育并存活，没有明显异常。为了尝试确定XT2的潜在底物，我们通过高压液相色谱和质谱法从XT2敲除小鼠中筛选了尿液，发现甘氨酸的浓度明显升高。为了研究甘氨酸的处理，向XT2 + / + 和XT2 ？/？小鼠注射放射性标记的甘氨酸，并收集尿液样本以监测甘氨酸的排泄。 2小时后，发现XT2 ？/？小鼠的甘氨酸排泄量几乎是XT2 + / + 对照的两倍（ P = 0.03 ）。为了确定XT2转运蛋白的缺失是否会影响钠和液体的体内稳态，我们通过计算机化的尾套测压法测量了收缩压。 XT2 ？/？小鼠的收缩压（127±3 mmHg）明显高于野生型对照组（114±2 mmHg; P <0.001）。在高盐和低盐喂养下，收缩压的这种差异得以维持。为了检查血压的变化与甘氨酸处理的缺陷是否相关，我们在补充甘氨酸的饮食中测量了XT2 ？/？小鼠的收缩压。甘氨酸负荷导致XT2 ？/？小鼠的收缩压从127±3 mmHg降至115±3 mmHg（ P <0.001），该水平实际上与该水平相同野生型对照。这些数据表明，XT2孤儿转运蛋白参与了甘氨酸的重吸收，并且这种转运蛋白的缺乏足以引起高血压。

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