TY - JOUR
T1 - ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney
AU - Naguro, Isao
AU - Umeda, Tsuyoshi
AU - Kobayashi, Yumie
AU - Maruyama, Junichi
AU - Hattori, Kazuki
AU - Shimizu, Yutaka
AU - Kataoka, Keiichiro
AU - Kim-Mitsuyama, Shokei
AU - Uchida, Shinichi
AU - Vandewalle, Alain
AU - Noguchi, Takuya
AU - Nishitoh, Hideki
AU - Matsuzawa, Atsushi
AU - Takeda, Kohsuke
AU - Ichijo, Hidenori
N1 - Funding Information:
This work was supported by KAKENHI from JSPS and MEXT, Global Center of Education and Research for Chemical Biology of the Diseases, the ‘Understanding of molecular and environmental bases for brain health’ conducted under the Strategic Research Programme for Brain Sciences by MEXT, the Advanced research for medical products Mining Programme of the National Institute of Biomedical Innovation, the Uehara Memorial Foundation, the Cosmetology Research Foundation and the Tokyo Biochemical Research Foundation. We thank T. Moriguchi and H. Shibuya for providing the SPAK CT construct, T. Chiba, S. Murata and K. Tanaka for the help to generate ASK3 KO mice and K. Tashiro, Y. Kohno, H. Iizuka and S. Tanabe for the excellent technical assistance and generation of antibodies. We also thank all of the members of Cell Signaling Laboratory for critical discussions.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms2283
DO - 10.1038/ncomms2283
M3 - Article
C2 - 23250415
AN - SCOPUS:84871765729
SN - 2041-1723
VL - 3
JO - Nature Communications
JF - Nature Communications
M1 - 1285
ER -