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, Hidenori Ichijo

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Article number1285
JournalNature communications
Volume3
DOIs
Publication statusPublished - 2012 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney'. Together they form a unique fingerprint.

  • Cite this

    Naguro, I., Umeda, T., Kobayashi, Y., Maruyama, J., Hattori, K., Shimizu, Y., Kataoka, K., Kim-Mitsuyama, S., Uchida, S., Vandewalle, A., Noguchi, T., Nishitoh, H., Matsuzawa, A., Takeda, K., & Ichijo, H. (2012). ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney. Nature communications, 3, [1285]. https://doi.org/10.1038/ncomms2283