title: ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney.
abstract: 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.
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Naguro
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Umeda
authors.forename: Yumie
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Junichi
authors.initials: J
authors.lastname: Maruyama
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hattori
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kataoka
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.forename: Alain
authors.initials: A
authors.lastname: Vandewalle
authors.forename: Takuya
authors.initials: T
authors.lastname: Noguchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishitoh
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000502:physiology*; D007684:Kidney Tubules / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009997:Osmotic Pressure / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D015778:Minor Histocompatibility Antigens; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse; D020930:MAP Kinase Kinase Kinases; C550123:MAP3K15 protein, human; C581564:Map3k15 protein, mouse