Analysis of abnormal chloride transport in the pathogenesis of renal electrolyte disorders
| Project/Area Number |
18390246
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
UCHIDA Shinichi Tokyo Medical and Dental University, Deptt of Nephrology, Associate Professor (50262184)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,750,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2007: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | phosphorylation / hypertension / pseudohypoaldosteronism / Bartter syndrome / knockin mouse / thiazide / claudin / Na-Cl共輸送体 |
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| Research Abstract |
1) Pseudohypoaldosteronism type II (PHAII) is an autosomal-dominant disorder characterized by hyperkalemia, acidosis, and hypertension. Studies of monogenetic hypertensive diseases such as PHAII will provide insight into the mechanisms underlying blood pressure regulation. We clarified the pathogenesis of PHAII by generating Wnk4^<561A> knockin mice, an ideal mouse model of PHAII. We clearly showed that the major pathogenesis of PHAII is the activation of the phosphorylation cascade of the WNK4-OSR1/SPAK-NaCl cotransporter (NCC).
2) CIC-K chloride channels belong to the CLC chloride channel family and play an important role in transepithelial chloride transport in the kidney. To be functional, CIC-K channels need to be translocated to the plasma membranes after synthesis : the translocation requires the binding to its b-subunit, barttin. The binding interaction between barttin and CIC-K channels has not been characterized, although the crystal structure of CLC was resolved. In the present study, we sought to clarify the binding sites of barttin in CIC-K2 by co-immunoprecipitation and immunofluorescence microscopy using various CIC-K2 mutants. We found that barttin was able to bind to the domains that constitute the outer lateral surfaces of CIC-K2. This information regarding the binding sites will be useful for designing a new class of diuretics or anti-hypertensive agents that inhibit the interaction of CIC-K and barttin.
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Report
(3 results)
Research Products
(21 results)
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[Journal Article] Molecular pathogenesis of pseudohypoaldosteronism type II : generation and analysis of a Wnk4(D561A/+) knockin mouse model2007
Author(s)
Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin SH, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S.
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Journal Title
Cell Metab 5(5)
Pages: 331-44
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Generation and analysis of Wnk4D561A/+ knock-in mice2007
Author(s)
Yang S, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin S, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S.
Organizer
ISN - Nature Genetics Forefronts Symposium on Nephrogenetics : from Development to Physiology
Place of Presentation
Danvers, USA
Description
「研究成果報告書概要(欧文)」より
Related Report
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