Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II
Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II
复制标题
膳食盐摄入通过血管紧张素 II 调节小鼠主动脉 WNK3-SPAK-NKCC1 磷酸化级联
DOI：
10.1161/hypertensionaha.113.01543
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发表时间：
2013
期刊：
影响因子：
8.3
通讯作者：
Uchida S
中科院分区：
文献类型：
--
作者：
Zeniya M;Sohara E;Kita S;Iwamoto T;Susa K;Mori T;Oi K;Chiga M;Takahashi D;Yang SS;Lin SH;Rai T;Sasaki S;Uchida S
Na-K-Cl协同转运体亚型1（NKCC 1）参与调节血管平滑肌细胞收缩。近年来，研究发现血管平滑肌细胞中的无赖氨酸激酶（WNK）-STE 20/SPS 1相关的脯氨酸/丙氨酸富激酶（SPAK）-NKCC 1磷酸化级联反应在调节血管张力中起重要作用。在这项研究中，我们研究了小鼠主动脉组织中的WNK-SPAK-NKCC 1级联反应是否受饮食盐摄入量的调节及其机制。SPAK和NKCC 1的磷酸化在高盐喂养的小鼠的主动脉中显著降低，在低盐喂养的小鼠的主动脉中增加，表明主动脉中的WNK-SPAK-NKCC 1磷酸化级联确实受到饮食盐摄入的调节。急性和慢性血管紧张素II输注增加了小鼠主动脉中SPAK和NKCC 1的磷酸化。此外，血管紧张素II 1型受体拮抗剂缬沙坦可抑制低盐饮食诱导的SPAK和NKCC 1磷酸化，表明血管紧张素II通过血管紧张素II 1型受体激活WNK-SPAK-NKCC 1磷酸化级联反应。然而，低盐饮食和血管紧张素II一起没有增加WNK 3敲除小鼠主动脉中SPAK和NKCC 1的磷酸化，表明低盐饮食和血管紧张素II诱导的WNK-SPAK-NKCC 1磷酸化级联的激活依赖于WNK 3。事实上，血管紧张素II诱导的血压升高在WNK 3敲除小鼠中减少。此外，在WNK 3敲除小鼠中观察到肠系膜动脉中对血管紧张素II的反应降低。我们的数据还阐明了血管紧张素II调节血管紧张性的新机制。因此，抑制这种级联反应可能是高血压的一种新的治疗靶点。
Na–K–Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)–STE20/SPS1-related proline/alanine-rich kinase (SPAK)–NKCC1 phosphorylation cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK–SPAK–NKCC1 cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt–fed mice and was increased in the aorta in low-salt–fed mice, indicating that the WNK–SPAK–NKCC1 phosphorylation cascade in the aorta was indeed regulated by dietary salt intake. Acute and chronic angiotensin II infusion increased phosphorylation of SPAK and NKCC1 in the mouse aorta. In addition, valsartan, an antagonist of angiotensin II type 1 receptor, inhibited low-salt diet–induced phosphorylation of SPAK and NKCC1, demonstrating that angiotensin II activates the WNK–SPAK–NKCC1 phosphorylation cascade through the angiotensin II type 1 receptor. However, a low-salt diet and angiotensin II together did not increase phosphorylation of SPAK and NKCC1 in the aorta in WNK3 knockout mice, indicating that activation of the WNK–SPAK–NKCC1 phosphorylation cascade induced by a low-salt diet and angiotensin II is dependent on WNK3. Indeed, angiotensin II–induced increases in blood pressure were diminished in WNK3 knockout mice. In addition, decreased response to angiotensin II in the mesenteric arteries was observed in WNK3 knockout mice. Our data also clarified a novel mechanism for regulation of vascular tonus by angiotensin II. Inhibition of this cascade could, therefore, be a novel therapeutic target in hypertension.