ASK3 responds to osmotic stress and regulatesblood pressure by suppressing WNK1-SPAK/OSR1signaling in the kidney

摘要

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 tomaintain homoeostasis of body fluid. However, these processes are incompletely understoodin 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 toosmotic stress. We further demonstrate that ASK3 interacts with WNK1, mutation in whichcauses an inherited form of hypertension in humans. Knockdown of Ask3 by short interferingRNA enhances the activation of the WNK1-SPAK/OSR1 signalling pathway. Moreover, Ask3knockout mice exhibit a hypertensive phenotype, in addition to hyperactivation ofSPAK/OSR1 in renal tubules. Our results suggest that ASK3 is a unique bidirectionalresponder to osmotic stress and that it has a role in the control of blood pressure as anupstream suppressor of the WNK1-SPAK/OSR1 signalling pathway.