WNK kinase links insulin with salt-sensitive hypertension

2013 Fiscal Year Final Research Report

• Project/Area Number: 24790836
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: SOHARA EISEI 東京医科歯科大学, 医学部附属病院, 講師 (90510355)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: インスリン / メタボリック症候群 / 塩分感受性高血圧 / WNKキナーゼ / サイアザイド / 水・電解質代謝学

Research Abstract

We found renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. In SPAK/OSR1 knock-in db/db mice, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC. Moreover, we found that Increased NCC phosphorylation is regulated by the PI3K/Akt signaling cascade in the kidney in response to hyperinsulinemia. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome. We also found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 mutation, due to impaired KLHL3-Cullin3 mediated ubiquitination.

Research Products

• [Journal Article] Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice (2014)
  • Author(s): Susa K, Sohara E, Rai T, Zeniya M, Mori Y, Mori T, Chiga M, Nomura N, Nishida H, Takahashi D, Isobe K, Inoue Y, Takeishi K, Takeda N, Sasaki S, Uchida S
  • Journal Title: Hum Mol Genet Volume: (in press)
  • DOI: 10.1093/hmg/ddu217
  • Peer Reviewed
• [Journal Article] Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model (2014)
  • Author(s): Inoue Y, Sohara E, Kobayashi K, Chiga M, Rai T, Ishibashi K, Horie S, Su X, Zhou J, Sasaki S, Uchida S
  • Journal Title: J Am Soc Nephrol Volume: (in press)
  • DOI: 10.1681/ASN.2013060614
  • Peer Reviewed
• [Journal Article] WNK4 is the major WNK kinase positively regulating NCC in the mouse kidney. (2014)
  • Author(s): Takahashi D, Mori T, Nomura N, Khan MZ, Araki Y, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S
  • Journal Title: Biosci Rep Volume: (in press)
  • DOI: 10.1042/BSR20140047
  • Peer Reviewed
• [Journal Article] Regulation of with-no-lysine kinase signaling by Kelch-like proteins (2014)
  • Author(s): Uchida S, Sohara E, Rai T, Sasaki S
  • Journal Title: Biol Cell Volume: 106(2) Pages: 45-56
  • DOI: 10.1111/boc.201300069
  • Peer Reviewed
• [Journal Article] Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II (2013)
  • Author(s): Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S
  • Journal Title: Hypertension Volume: 62(5) Pages: 872-878
  • DOI: 10.1161/HYPERTENSIONAHA.113.01543
  • Peer Reviewed
• [Journal Article] Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension (2013)
  • Author(s): Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S
  • Journal Title: Cell Rep Volume: 3(3) Pages: 858-68
  • DOI: 10.1016/j.celrep.2013.02.024
  • Peer Reviewed
• [Journal Article] Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter (NCC) measurement. (2013)
  • Author(s): Isobe K, Mori T, Asano T, Kawaguchi H, Nonoyama S, Kumagai N, Kamada F, Morimoto T, Hayashi M, Sohara E, Rai T, Sasaki S, Uchida S
  • Journal Title: Am J Physiol Renal Physiol Volume: 305(9) Pages: F1374-81
  • DOI: 10.1152/ajprenal.00208.2013
  • Peer Reviewed
• [Journal Article] Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy (2013)
  • Author(s): Mori T, Kikuchi E, Watanabe Y, Fujii S, Ishigami-Yuasa M, Kagechika H, Sohara E, Rai T, Sasaki S, Uchida S
  • Journal Title: Biochem J Volume: 455 Pages: 339-45
  • DOI: 10.1042/BJ20130597.
  • Peer Reviewed
• [Journal Article] Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms (2013)
  • Author(s): Mori Y, Wakabayashi M, Mori T, Araki Y, Sohara E, Rai T, Sasaki S, Uchida S
  • Journal Title: Biochem Biophys Res Commun Volume: 439 Pages: 30-4
  • DOI: 10.1016/j.bbrc.2013.08.035.
  • Peer Reviewed
• [Journal Article] KLHL2 interacts with and ubiquitinates WNK kinases (2013)
  • Author(s): Takahashi D, Mori T, Wakabayashi M, Mori Y, Susa K, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S
  • Journal Title: Biochem Biophys Res Commun Volume: 437(3) Pages: 457-62
  • DOI: 10.1016/j.bbrc.2013.06.104
  • Peer Reviewed
• [Journal Article] Immunolocalization and translocation of aquaporin-5 water channel in sweat glands (2013)
  • Author(s): Inoue R, Sohara E, Rai T, Satoh T, Yokozeki H, Sasaki S, Uchida S
  • Journal Title: J Dermatol Sci Volume: 70(1) Pages: 26-33
  • DOI: 10.1016/j.jdermsci.2013.01.013
  • Peer Reviewed
• [Journal Article] Treatment with 17-allylamino-17-demethoxygeldanamycin ameliorated symptoms of Bartter syndrome type IV caused by mutated Bsnd in mice (2013)
  • Author(s): Nomura N, Kamiya K, Ikeda K, Yui N, Chiga M, Sohara E, Rai T, Sasaki S, Uchida S
  • Journal Title: Biochem Biophys Res Commun Volume: 441 Pages: 544-49
  • DOI: 10.1016/j.bbrc.2013.10.129
  • Peer Reviewed
• [Journal Article] Beta2-adrenargic receptor, WNK4 and Na-Cl co-transporter signal cascade : Does it exist in the in vivo kidney? (2012)
  • Author(s): Uchida S, Chiga M, Sohara E, Rai T, Sasaki S
  • Journal Title: Nat Med Volume: 18(9) Pages: 1324-5
  • DOI: 10.1038/nm.2809
  • Peer Reviewed
• [Journal Article] PI3K/Akt Signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice (2012)
  • Author(s): Nishida H, Sohara E, Nomura N, Chiga M, Alessi DR, Rai T, Sasaki S, Uchida S
  • Journal Title: Hypertension Volume: 60(4) Pages: 981-90
  • DOI: 10.1161/HYPERTENSIONAHA.112.201509
  • Peer Reviewed
• [Journal Article] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination (2012)
  • Author(s): Hossain-Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, Wakabayashi M, Oi K, Rai T, Sasaki S, Uchida S
  • Journal Title: Biochem Biophys Res Commun. Volume: 425(2) Pages: 456-61
  • DOI: 10.1016/j.bbrc.2012.07.124
  • Peer Reviewed
• [Journal Article] A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo (2012)
  • Author(s): Oi K, Sohara E, Rai T, Misawa M, Chiga M, Alessi DR, Sasaki S, Uchida S
  • Journal Title: Biol Open Volume: 1 Pages: 120-127
  • DOI: 10.1242/bio.2011048.
  • Peer Reviewed
• [Journal Article] Effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/ NKCC1 /NKCC2 signal cascade in the kidney and blood vessels (2012)
  • Author(s): Susa K, Kita S, Iwamoto T, Yang SS, Lin SH, Ohta A, Sohara E, Rai T, Sasaki S, Alessi DR, Uchida S
  • Journal Title: Clin Exp Nephrol Volume: 16(4) Pages: 530-8
  • DOI: 10.1016/j.bbrc.2012.09.130
  • Peer Reviewed
• [Journal Article] Involvement of aquaporin-7 in the cutaneous primary immune response through modulation of antigen uptake and migration in dendritic cells (2012)
  • Author(s): Hara-Chikuma M, Sugiyama Y, Kabashima K, Sohara E, Uchida S, Sasaki S, Inoue S, Miyachi Y
  • Journal Title: FASEB J Volume: 26(1) Pages: 211-8
  • DOI: 10.1096/fj.11-186627
  • Peer Reviewed
• [Journal Article] Severe hyperparathyroidism in a pre-dialysis chronic kidney disease patient treated with a very low protein diet (2012)
  • Author(s): Ohta E, Akazawa M, Noda Y, Mandai S, Naito S, Ohta A, Sohara E, Okado T, Rai T, Uchida S, Sasaki S
  • Journal Title: J Bone Miner Metab Volume: 30(2) Pages: 238-42
  • DOI: 10.1007/s00774-011-0320-6.
  • Peer Reviewed
• [Presentation] WNK3 Regulates Blood Pressure Through the Regulation of Vascular OSR1/SPAK-NKCC1 Phosphorylation Cascade (2013)
  • Author(s): Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S
  • Organizer: The 46th Annual Meeting of American Societyof Nephrology
  • Place of Presentation: Atlanta
  • Year and Date: 2013-11-09
• [Presentation] Low salt intake decreased transcription and protein level of KLHL3 in mouse kidney (2013)
  • Author(s): Susa K, Sohara E, Zeniya M, Rai T, Sasaki S, Uchida S
  • Organizer: The 46th Annual Meeting of American Society of Nephrology
  • Place of Presentation: Atlanta
  • Year and Date: 2013-11-08
• [Presentation] Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in AQP11-Knockout Mice (2013)
  • Author(s): Inoue Y, Sohara E, Kobayashi K, Rai T, Ishibashi K, Horie S, Su X, Zhou J, Sasaki S, Uchida S
  • Organizer: Renal Week 2013, American Society ofNephrology
  • Place of Presentation: Atlanta
  • Year and Date: 2013-11-07
• [Presentation] Investigation of Pathophysiology of RenalSodium and Water Transport Disorders (2013)
  • Author(s): 蘇原映誠
  • Organizer: 日本腎臓学会平成25年度大島賞受賞講演
  • Place of Presentation: 東京
  • Year and Date: 2013-05-10
• [Presentation] WNKキナーゼによる血圧調節機構 (2013)
  • Author(s): 蘇原映誠
  • Organizer: 第42回新潟腎カンファランス
  • Place of Presentation: 新潟
  • Year and Date: 2013-02-21
• [Presentation] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination (2012)
  • Author(s): Hossain Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, Wakabayashi M, Naito S, Oi K, Rai T, Sasaki S, Uchida S
  • Organizer: The 45th Annual Meeting of the American Society of Nephrology
  • Place of Presentation: SanDiego, California
  • Year and Date: 2012-11-02
• [Presentation] Dietary salt intake and angiotensin II regulates WNK-SPAK-NKCC1 phosphorylation cascade in mouse aorta (2012)
  • Author(s): Zeniya M, Sohara E, Oi K, Chiga M, Susa K, Mori T, Rai T,Sasaki S, Uchida S
  • Organizer: The 45th Annual Meeting of American Society of Nephrology
  • Place of Presentation: San Diego
  • Year and Date: 2012-11-02
• [Presentation] WNK4-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone (2012)
  • Author(s): Susa K, Sohara E, Isobe K, Chiga M, Rai T, Sasaki S, Uchida S
  • Organizer: The 45th Annual Meeting of American Society of Nephrology
  • Place of Presentation: San Diego
  • Year and Date: 2012-11-02
• [Presentation] Impaired trafficking of polycystin-1 may be a key mechanism of cyst formation in the aquaporin-11 knockout mouse (2012)
  • Author(s): Inoue Y, Sohara E, Kobayashi K, Rai T, Ishibashi K, Sasaki S, Shinichi U
  • Organizer: The 45st Annual Meeting of American Society ofNephrology
  • Place of Presentation: San Diego
  • Year and Date: 2012-11-02
• [Presentation] Development of sandwich enzyme linked immunosorbent assay (ELISA) for measurement of urinary total and phosphorylated Na-Clcotransporter (NCC) protein (2012)
  • Author(s): Isobe K, Sohara E, Rai T, Sasaki S, Uchida S
  • Organizer: The 45th Annual meeting of American Society of Nephrology
  • Place of Presentation: San Diego
  • Year and Date: 2012-11-02
• [Presentation] WNKキナーゼによる塩分調節機構 (2012)
  • Author(s): 蘇原映誠
  • Organizer: 第34回腎臓セミナー
  • Year and Date: 2012-08-25