WNK kinase links insulin with salt-sensitive hypertension

我们在高胰岛素血症代谢综合征db/db小鼠模型中发现肾脏WNK-OSR 1/SPAK-NCC级联激活。在SPAK/OSR 1基因敲入db/db小鼠中，NCC磷酸化增加和血压升高被完全纠正，表明WNK激酶对SPAK和OSR 1的磷酸化是NCC活化和磷酸化增加所必需的。此外，我们发现，增加的NCC磷酸化是由PI 3 K/Akt信号级联反应在肾脏中响应于高胰岛素血症而调节的。这种机制可能在人类高胰岛素血症（如代谢综合征）中盐敏感性高血压的发病机制中发挥作用。我们还发现，由于KLHL 3-Cullin 3介导的泛素化受损，WNK 1和WNK 4激酶的蛋白表达水平增加通过KLHL 3突变引起PHAII。

We found renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. In SPAK/OSR1 knock-in db/db mice, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC. Moreover, we found that Increased NCC phosphorylation is regulated by the PI3K/Akt signaling cascade in the kidney in response to hyperinsulinemia. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome. We also found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 mutation, due to impaired KLHL3-Cullin3 mediated ubiquitination.