Vesicle-associated Membrane Protein 3 (VAMP3) Mediates Constitutive Trafficking of the Renal Co-transporter NKCC2 in Thick Ascending Limbs: ROLE IN RENAL FUNCTION AND BLOOD PRESSURE.
Vesicle-associated Membrane Protein 3 (VAMP3) Mediates Constitutive Trafficking of the Renal Co-transporter NKCC2 in Thick Ascending Limbs: ROLE IN RENAL FUNCTION AND BLOOD PRESSURE.
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DOI：
10.1074/jbc.m116.735167
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发表时间：
2016-10-14
期刊：
影响因子：
--
通讯作者：
Ortiz PA
中科院分区：
文献类型：
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作者：
Caceres PS;Mendez M;Haque MZ;Ortiz PA
粗升支（TAL）的肾细胞通过顶端Na+/K+/2Cl−协同转运蛋白NKCC 2重吸收NaCl。NKCC 2向根尖表面的运输调节NKCC 2介导的NaCl吸收和血压。NKCC 2到达顶面的分子机制及其在肾功能和血压维持中的作用尚不清楚。在这里，我们报告NKCC 2与囊泡融合蛋白VAMP 3相互作用，它们共定位于TAL顶端表面。我们观察到，在体内沉默VAMP 3阻断了组成型NKCC 2胞吐递送，减少了TAL顶端表面的NKCC 2的量。cAMP刺激的NKCC 2胞吐递送不需要VAMP 3。此外，小鼠中VAMP 3的遗传缺失降低了TAL中NKCC 2的总表达并降低了血压。与这些结果一致，VAMP 3敲除小鼠的水和电解质的尿排泄量较高，产生更多稀释的尿液。我们的结论是，VAMP 3与NKCC 2相互作用，并介导其组成性胞外传递到顶端表面。此外，VAMP 3是正常NKCC 2表达、肾功能和血压所必需的。
Renal cells of the thick ascending limb (TAL) reabsorb NaCl via the apical Na+/K+/2Cl− co-transporter NKCC2. Trafficking of NKCC2 to the apical surface regulates NKCC2-mediated NaCl absorption and blood pressure. The molecular mechanisms by which NKCC2 reaches the apical surface and their role in renal function and maintenance of blood pressure are poorly characterized. Here we report that NKCC2 interacts with the vesicle fusion protein VAMP3, and they co-localize at the TAL apical surface. We observed that silencing VAMP3 in vivo blocks constitutive NKCC2 exocytic delivery, decreasing the amount of NKCC2 at the TAL apical surface. VAMP3 is not required for cAMP-stimulated NKCC2 exocytic delivery. Additionally, genetic deletion of VAMP3 in mice decreased total expression of NKCC2 in the TAL and lowered blood pressure. Consistent with these results, urinary excretion of water and electrolytes was higher in VAMP3 knock-out mice, which produced more diluted urine. We conclude that VAMP3 interacts with NKCC2 and mediates its constitutive exocytic delivery to the apical surface. Additionally, VAMP3 is required for normal NKCC2 expression, renal function, and blood pressure.