WNK kinase links insulin with salt-sensitive hypertension
Project/Area Number |
24790836
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Kidney internal medicine
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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)
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Project Period (FY) |
2012-04-01 – 2014-03-31
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Project Status |
Completed (Fiscal Year 2013)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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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 / 肥満 / WNKシグナル / WNK / NCC / 高血圧 |
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.
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Report
(3 results)
Research Products
(54 results)
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[Journal Article] Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice2014
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
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Journal Title
Hum Mol Genet
Volume: (in press)
DOI
Related Report
Peer Reviewed
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[Journal Article] Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model2014
Author(s)
Inoue Y, Sohara E, Kobayashi K, Chiga M, Rai T, Ishibashi K, Horie S, Su X, Zhou J, Sasaki S, Uchida S
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Journal Title
J Am Soc Nephrol
Volume: (in press)
DOI
Related Report
Peer Reviewed
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[Journal Article] Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II2013
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
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Journal Title
Hypertension
Volume: 62(5)
Pages: 872-878
DOI
Related Report
Peer Reviewed
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[Journal Article] Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension2013
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
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Journal Title
Cell Rep
Volume: 3(3)
Pages: 858-68
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
Am J Physiol Renal Physiol
Volume: 305(9)
Pages: F1374-81
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Cell Rep.
Volume: 3
Pages: 858-68
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Hypertension
Volume: 62
Pages: 872-8
DOI
Related Report
Peer Reviewed
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[Journal Article] Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter 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.
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Journal Title
Am J Physiol Renal Physiol.
Volume: 305
Pages: F1374-81
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Cell Rep.
Volume: 3
Pages: 858-868
DOI
Related Report
Peer Reviewed
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[Journal Article] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination2012
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
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Journal Title
Biochem Biophys Res Commun.
Volume: 425(2)
Pages: 456-61
DOI
Related Report
Peer Reviewed
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[Journal Article] Effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/ NKCC1 /NKCC2 signal cascade in the kidney and blood vessels2012
Author(s)
Susa K, Kita S, Iwamoto T, Yang SS, Lin SH, Ohta A, Sohara E, Rai T, Sasaki S, Alessi DR, Uchida S
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Journal Title
Clin Exp Nephrol
Volume: 16(4)
Pages: 530-8
DOI
Related Report
Peer Reviewed
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[Journal Article] Severe hyperparathyroidism in a pre-dialysis chronic kidney disease patient treated with a very low protein diet2012
Author(s)
Ohta E, Akazawa M, Noda Y, Mandai S, Naito S, Ohta A, Sohara E, Okado T, Rai T, Uchida S, Sasaki S
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Journal Title
J Bone Miner Metab
Volume: 30(2)
Pages: 238-42
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
Clin Exp Nephrol.
Volume: 16
Pages: 530-538
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Biochem Biophys Res Commun
Volume: 425
Pages: 456-461
DOI
Related Report
Peer Reviewed
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[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 Society of Nephrology
Place of Presentation
Atlanta、アメリカ合衆国
Year and Date
20131107-20131110
Related Report
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[Presentation] WNK3 Regulates Blood Pressure Through the Regulation of Vascular OSR1/SPAK-NKCC1 Phosphorylation Cascade2013
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
Related Report
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[Presentation] Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in AQP11-Knockout Mice2013
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
Related Report
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[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
San Diego,USA
Year and Date
20121030-20121103
Related Report
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[Presentation] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination2012
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
Related Report
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