Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
PLoS One. 2013 Sep 11;8(9):e72969. doi: 10.1371/journal.pone.0072969. eCollection 2013.
Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na(+)-Cl(-) cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo. Wnk4 (D561A/+) mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP-Osr1 (-/-)) and Spak knockout (Spak (-/-)) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 (D561A/+), KSP-Osr1 (-/-), and Spak (-/-) mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 (D561A/+).KSP-Osr1 (-/-) remained phenotypically PHA II while Wnk4 (D561A/+).Spak (-/-) mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 (D561A/+) and Wnk4 (D561A/+).KSP-Osr1 (-/-) mice while phosphorylated Ncc normalized in Wnk4 (D561A/+).Spak (-/-) mice. Furthermore, Wnk4 (D561A/+).KSP-Osr1 (-/-) mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 (D561A/+).Spak (-/-) mice exhibited normal responses. Wnk4(D561A/+).Spak (-/-).KSP-Osr1 (-/-) triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.
OSR1（氧化应激响应激酶-1）/SPAK[STE20（无菌 20）/SPS1 相关脯氨酸/丙氨酸丰富激酶]-NCC（Na（+）-Cl（-）共转运蛋白）信号级联的刺激在 WNK [无赖氨酸（K）]激酶 4 D561A 基因敲入假醛固酮症 II 型（PHA II）小鼠模型中发挥重要作用，其特征为盐敏感性高血压和高钾血症。本研究的目的是研究 Osr1 和 Spak 在体内 PHA II 发病机制中的各自作用。将 Wnk4（D561A/+）小鼠与肾小管特异性（KSP）Osr1 敲除（KSP-Osr1（-/-））和 Spak 敲除（Spak（-/-））小鼠杂交。检查血压、血浆和尿液生化指标以及肾脏中相关蛋白的表达。Wnk4（D561A/+）、KSP-Osr1（-/-）和 Spak（-/-）小鼠分别再现了 PHA II、Bartter 样综合征和 Gitelman 综合征的表型。Wnk4（D561A/+）.KSP-Osr1（-/-）仍然表现出 PHA II 表型，而 Wnk4（D561A/+）.Spak（-/-）小鼠成为血压正常且缺乏 PHA II 表型。磷酸化 Spak 和 Ncc 在 Wnk4（D561A/+）和 Wnk4（D561A/+）.KSP-Osr1（-/-）小鼠中均增加，而 Wnk4（D561A/+）.Spak（-/-）小鼠中磷酸化 Ncc 恢复正常。此外，Wnk4（D561A/+）.KSP-Osr1（-/-）小鼠在噻嗪类利尿剂的作用下表现出过度的盐排泄，而 Wnk4（D561A/+）.Spak（-/-）小鼠则表现出正常反应。Wnk4（D561A/+）.Spak（-/-）.KSP-Osr1（-/-）三重突变小鼠血压较低，磷酸化 Ncc 减少。SPAK 和 OSR1 都在维持血压方面很重要，但 SPAK-NCC 的激活在 PHA II 中起主导作用。SPAK 可能是与 WNK4 激活相关的盐敏感性高血压相关疾病的治疗靶点。
