Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Nat Commun. 2012;3:1285. doi: 10.1038/ncomms2283.
Changes in the osmolality of body fluids pose a serious danger to cells and living organisms, which have developed cellular systems to sense and respond to osmotic stress and to maintain homoeostasis of body fluid. However, these processes are incompletely understood in mammals. Here we show that apoptosis signal-regulating kinase 3 (ASK3) is predominantly expressed in the kidney and alters its kinase activity bidirectionally in response to osmotic stress. We further demonstrate that ASK3 interacts with WNK1, mutation in which causes an inherited form of hypertension in humans. Knockdown of Ask3 by short interfering RNA enhances the activation of the WNK1-SPAK/OSR1 signalling pathway. Moreover, Ask3 knockout mice exhibit a hypertensive phenotype, in addition to hyperactivation of SPAK/OSR1 in renal tubules. Our results suggest that ASK3 is a unique bidirectional responder to osmotic stress and that it has a role in the control of blood pressure as an upstream suppressor of the WNK1-SPAK/OSR1 signalling pathway.
体液渗透压的变化对细胞和生物体构成严重威胁，细胞和生物体已经进化出细胞系统来感知和应对渗透胁迫，并维持体液的内稳态。然而，哺乳动物中这些过程还不完全清楚。在这里，我们发现凋亡信号调节激酶 3（ASK3）主要在肾脏中表达，并在应对渗透压胁迫时双向改变其激酶活性。我们进一步证明 ASK3 与 WNK1 相互作用，WNK1 的突变会导致人类遗传性高血压。通过短干扰 RNA 敲低 Ask3 会增强 WNK1-SPAK/OSR1 信号通路的激活。此外，ASK3 基因敲除小鼠表现出高血压表型，此外，肾脏小管中 SPAK/OSR1 的过度激活。我们的研究结果表明，ASK3 是一种对渗透压胁迫的独特双向反应蛋白，作为 WNK1-SPAK/OSR1 信号通路的上游抑制因子，在血压控制中发挥作用。
