Disruption of the with no lysine kinase-STE20-proline alanine-rich kinase pathway reduces the hypertension induced by angiotensin II.
Disruption of the with no lysine kinase-STE20-proline alanine-rich kinase pathway reduces the hypertension induced by angiotensin II.
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DOI：
10.1097/hjh.0000000000001554
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发表时间：
2018-03
影响因子：
4.9
通讯作者：
Gamba G
中科院分区：
文献类型：
--
作者：
Cervantes-Perez LG;Castaneda-Bueno M;Jimenez JV;Vazquez N;Rojas-Vega L;Alessi DR;Bobadilla NA;Gamba G
血管紧张素II(AngII)是一种多肽激素，其降压作用依赖于其肾内作用和肾脏Na-Cl协同转运体(NCC)的激活，Angii要求没有赖氨酸激酶/STE20-Pro-丙氨酸激酶(WNK/SPAK)信号通路的完整性。在这里，我们分析了WNK/SPAK通路的完整性是否是血管紧张素转换酶诱导动脉高压所必需的。我们在SPAKT243A/243A敲入小鼠中检测了血管紧张素转换酶和醛固酮对血压和pNCC/NCC比值的影响，在SPAKT243A/243A敲入小鼠中，WNK激酶不能激活pNCC，从而也就是NCC。血管紧张素转换酶抑制剂或醛固酮分别以每天1440或700 μg/kg的速度静脉滴注，连续14天。在给予激素的过程中，给予醛固酮治疗的小鼠暴露在1%的氯化钠饮用水中。用放射遥测仪测量动脉血压。我们观察到，在SPAK基因敲入小鼠中，血管紧张素转换酶诱导的高血压效应显著降低，并且与血管紧张素转换酶诱导的NCC磷酸化缺失有关。相反，醛固酮的降压作用被增强，并与对阿米洛利的反应增加有关，但与噻嗪类利尿剂无关，并未显著增加NCC的磷酸化。我们的数据表明，Angii诱导的高血压至少部分地需要通过WNK/Spak信号通路激活NCC，而醛固酮诱导的高血压依赖于上皮钠通道的激活，这种激活不依赖于WNK/Spak。SPAK基因敲除小鼠是区分血管紧张素转换酶和醛固酮对远端肾单位影响的有用模型。
Supplemental Digital Content is available in the text The hypertensive effect of angiotensin II (AngII), a peptide hormone, is dependent on its intrarenal actions and the activation of the renal Na–Cl cotransporter (NCC), by AngII requires integrity of the with no lysine kinase/STE20-proline alanine-rich kinase (WNK/SPAK) signaling pathway. Here, we analyzed if the integrity of the WNK/SPAK pathway is required for AngII infusion to induce arterial hypertension. We tested the effect of AngII or aldosterone administration on the blood pressure and on pNCC/NCC ratio in SPAKT243A/243A knock-in mice in which the kinase and thus NCC cannot be activated by WNK kinases. AngII or aldosterone was infused at 1440 or 700 μg/kg per day, respectively, for 14 days using osmotic minipumps. The aldosterone-treated mice were exposed to NaCl drinking water (1%) during the hormone administration. The arterial blood pressure was assessed using radiotelemetry. We observed that in the SPAK knock-in mice, the AngII-induced hypertensive effect was significantly reduced and associated with an absence of AngII-induced NCC phosphorylation. In contrast, the hypertensive effect of aldosterone was enhanced and was related with an increased response to amiloride, but not to thiazide-type diuretics, without a significant increase in NCC phosphorylation. Our data suggest that AngII-induced hypertension requires, at least partly, NCC activation via the WNK/SPAK signaling pathway, whereas aldosterone-induced hypertension depends on epithelial sodium channel activation in a WNK/SPAK-independent manner. SPAK knock-in mice emerge as a useful model to distinguish between the effects of AngII and aldosterone on distal nephrons.