ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney

Isao Naguro, Tsuyoshi Umeda, Yumie Kobayashi, Junichi Maruyama, Kazuki Hattori, Yutaka Shimizu, Keiichiro Kataoka, Shokei Kim-Mitsuyama, Shinichi Uchida, Alain Vandewalle, Takuya Noguchi, Hideki Nishitoh, Atsushi Matsuzawa, Kohsuke Takeda and Hidenori Ichijo ()
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Isao Naguro: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Tsuyoshi Umeda: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Yumie Kobayashi: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Junichi Maruyama: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Kazuki Hattori: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Yutaka Shimizu: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Keiichiro Kataoka: Kumamoto University Graduate School of Medical Sciences
Shokei Kim-Mitsuyama: Kumamoto University Graduate School of Medical Sciences
Shinichi Uchida: Graduate School of Medicine, Tokyo Medical and Dental University
Alain Vandewalle: Institut National de la Santé et de la Recherche Médicale (INSERM) U773, Université Paris Diderot
Takuya Noguchi: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Hideki Nishitoh: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Atsushi Matsuzawa: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Kohsuke Takeda: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Hidenori Ichijo: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms2283

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