Development of order-made treatment of hypertension by measurement of urinary transporters
Project/Area Number |
26670428
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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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, 医歯(薬)学総合研究科, 准教授 (90510355)
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Project Period (FY) |
2014-04-01 – 2016-03-31
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Project Status |
Completed (Fiscal Year 2015)
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Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | WNKキナーゼ / 塩分感受性 / AQP2 / リン / 塩分感受性高血圧 / KLHL3 |
Outline of Final Research Achievements |
Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and metabolic acidosis, and genes encoding with-no-lysine kinase 1 (WNK1) and WNK4 kinases are known to be responsible. Recently, Kelch-like 3 (KLHL3) and Cullin3, components of KLHL3-Cullin3 E3 ligase, were newly identified as responsible for PHAII. To investigate the pathogenesis of PHAII caused by KLHL3 mutation, we generated KLHL3R528H/+ knock-in mice. KLHL3R528H/+ knock-in mouse is an ideal mouse model of PHAII. Interestingly, the protein expression of both WNK1 and WNK4 was significantly increased in the KLHL3R528H/+ mouse kidney, confirming that increases in these WNK kinases activated the WNK-OSR1/SPAK-NCC phosphorylation cascade in KLHL3R528H/+ knock-in mice. Thus, we found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 R528H mutation due to impaired KLHL3-Cullin3-mediated ubiquitination.
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Report
(3 results)
Research Products
(42 results)
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[Journal Article] Comprehensive genetic testing approach for major inherited kidney diseases, using next-generation sequencing with a custom panel.2016
Author(s)
Mori T, Hosomichi K, Chiga M, Mandai S, Nakaoka H, Sohara E, Okado T, Rai T, Sasaki S, Inoue I, Uchida S.
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Journal Title
Clin Exp Nephrol.
Volume: 印刷中
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3.2015
Author(s)
Yoshizaki Y, Mori Y, Tsuzaki Y, Mori T, Nomura N, Wakabayashi M, Takahashi D, Zeniya M, Kikuchi E, Araki Y, Ando F, Isobe K, Nishida H, Ohta A, Susa K, Inoue Y, Chiga M, Rai T, Sasaki S, Uchida S, Sohara E.
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Journal Title
Biochem Biophys Res Commun.
Volume: 467
Issue: 2
Pages: 229-234
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Kelch-Like Protein 2 Mediates Angiotensin II-With No Lysine 3 Signaling in the Regulation of Vascular Tonus2015
Author(s)
Zeniya M, Morimoto N, Takahashi D, Mori Y, Mori T, Ando F, Araki Y, Yoshizaki Y, Inoue Y, Isobe K, Nomura N, Oi K, Nishida H, Sasaki S, Sohara E, Rai T, Uchida S
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Journal Title
J Am Soc Nephrol
Volume: 26
Issue: 9
Pages: 2129-2138
DOI
Related Report
Peer Reviewed
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[Journal Article] Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters2014
Author(s)
Kikuchi E, Mori T, Zeniya M, Isobe K, Ishigami-Yuasa M, Fujii S, Kagechika H, Ishihara T, Mizushima T, Sasaki S, Sohara E, Rai T, Uchida S
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Journal Title
J Am Soc Nephrol
Volume: 26
Issue: 7
Pages: 1525-1536
DOI
Related Report
Peer Reviewed
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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: 23 (19)
Issue: 19
Pages: 5052-60
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 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.
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Journal Title
J Am Soc Nephrol.
Volume: 25
Issue: 12
Pages: 2789-2799
DOI
Related Report
Peer Reviewed
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[Presentation] PKAとAktによるKLHL3リン酸化がWNK4との 結合を制御する.2015
Author(s)
吉崎幸, 蘇原映誠, 森崇寧, 若林麻衣, 高橋大栄, 銭谷慕子, 菊池絵梨子, 森雄太郎, 荒木 雄也, 安藤 史顕, 頼 建光, 佐々木 成, 内田 信一
Organizer
第 58 回日本腎臓学会学術総会
Place of Presentation
名古屋国際会議場(愛知県,名古屋)
Year and Date
2015-09-05
Related Report
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[Presentation] Molecular Pathogenesis of PHAII in KLHL3R528H/+ Knock-In Mice.2014
Author(s)
Susa K, Sohara E, Rai T, Zeniya M, Mori Y, Mori T, Chiga M, Takahashi D, Isobe K, Inoue Y, Takeda N, Sasaki S, Uchida S.
Organizer
The 47th Annual Meeting of American Society of Nephrology
Place of Presentation
Philadelphia、米国
Year and Date
2014-11-14 – 2014-11-16
Related Report
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[Presentation] KLHL2 mediates angiotensin II-WNK3 singaling involved in the regulation of vascular tonus2014
Author(s)
Zeniya M, Morimoto N, Takahashi D, Mori Y, Mori T, Ando F, Araki Y, Yoshizaki Y, Inoue Y, Ishobe K, Nomura N, Oi K, Nishida H, Sasaki S, Sohara E, Rai T, Uchida S.
Organizer
The 47th Annual Meeting of American Society of Nephrology
Place of Presentation
Philadelphia、米国
Year and Date
2014-11-14 – 2014-11-16
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[Presentation] WNK4は腎NCCの 正の制御因子である2014
Author(s)
高橋大栄, 森崇寧, 野村尚弘, Muhammad Zakir Hossain Khan, 荒木雄也, 銭谷慕子, 蘇原映誠, 頼建光, 佐々木成, 内田信一.
Organizer
第57回日本腎臓学会学術総会
Place of Presentation
横浜、パシフィコ横浜
Year and Date
2014-07-04 – 2014-07-06
Related Report
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[Presentation] Higher serum phosphorus levels at the initial visit predict more rapid decline in kidney function in pre-dialysis CKD patients in Japan2014
Author(s)
Kawasaki T, Ando R, Maeda Y, Arai Y, Sato H, Iimori S, Sohara E, Okado T, Rai T, Uchida S, Sasaki S.
Organizer
51st ERA-EDTA Congress.
Place of Presentation
Amsterdam、オランダ
Year and Date
2014-06-01 – 2014-06-03
Related Report
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