WNK kinase links salt-sensitive hypertension with obesity
Project/Area Number |
22790783
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Single-year Grants |
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, 助教 (90510355)
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Project Period (FY) |
2010 – 2011
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Project Status |
Completed (Fiscal Year 2011)
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Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | 水電解質 / WNK / インスリン / 高血圧 / 塩分再吸収 / NCC / SPAK / 塩分感受性 / 偽性低アルドステロン症 |
Research Abstract |
The NaCl cotransporter(NCC) is essential for sodium reabsorption at the distal convoluted tubules(DCT), and its phosphorylation increases its transport activity and apical membrane localization. Although insulin has been reported to increase sodium reabsorption in the kidney, the linkage between insulin and NCC phosphorylation has not yet been investigated. This study examined whether insulin regulates NCC phosphorylation. In cultured mpkDCT cells, insulin increased phosphorylation of STE20/SPS1-related proline-alanine-rich kinase(SPAK) and NCC in a dose-dependent manner. This insulin-induced phosphorylation of NCC was suppressed in WNK4 and SPAK knockdown cells. In addition, Ly294002, a PI3K inhibitor, decreased the insulin effect on SPAK and NCC phosphorylation, indicating that insulin induces phosphorylation of SPAK and NCC through PI3K and WNK4 in mpkDCT cells. Moreover, acute insulin administration to mice increased phosphorylation of oxidative stress-responsive kinase-1(OSR1), SPAK and NCC in the kidney. Time-course experiments in mpkDCT cells and mice suggested that SPAK is upstream of NCC in this insulin-induced NCC phosphorylation mechanism, which was confirmed by the lack of insulin-induced NCC phosphorylation in SPAK knockout mice. Moreover, insulin administration to WNK4 hypomorphic mice did not increase phosphorylation of OSR1, SPAK and NCC in the kidney, suggesting that WNK4 is also involved in the insulin-induced OSR1, SPAK and NCC phosphorylation mechanism in vivo. The present results demonstrated that insulin is a potent regulator of NCC phosphorylation in the kidney, and that WNK4 and SPAK are involved in this mechanism of NCC phosphorylation by insulin.
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Report
(3 results)
Research Products
(26 results)
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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
NAID
Related Report
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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
Bone Miner Metab
Volume: 30(2)
Pages: 238-42
NAID
Related Report
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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(4)
Issue: 4
Pages: 530-538
DOI
NAID
Related Report
Peer Reviewed
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[Journal Article] Impaired phosphorylation of Na(+)-K(+)-2Cl(-) cotransporter by oxidative stress-responsive kinase-1 deficiency manifests hypotension and Bartter-like syndrome2011
Author(s)
Lin SH, Yu IS, Jiang ST, Lin SW, Chu P, Chen A, Sytwu HK, Sohara E, Uchida S, Sasaki S, Yang SS.
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Journal Title
Natl Acad Sci USA
Volume: 108(42)
Pages: 17538-43
Related Report
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[Journal Article] Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney2011
Author(s)
Sohara E, Rai T, Yang SS, Ohta A, Naito S, Chiga M, Nomura N, Lin SH, Vandewalle A, Ohta E, Sasaki S, Uchida S.
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Journal Title
Related Report
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[Journal Article] Generation and analyses of R8L barttin knockin mouse2011
Author(s)
Nomura N, Tajima M, Sugawara N, Morimoto T, Kondo Y, Ohno M, Uchida K, Mutig K, Bachmann S, Soleimani M, Ohta E, Ohta A, Sohara E, Okado T, Rai T, Jentsch TJ, Sasaki S, Uchida S.
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Journal Title
Am J Physiol RenalPhysiol
Volume: 301(2)
Related Report
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[Journal Article] Calcium-alkali syndrome-like symptoms manifested by daily alphacalcidol and thiazide.2010
Author(s)
Satoh F, Okado T, Iwamoto M, Akita W, Wakabayashi M, Ohta A, Sohara E, Noda Y, Rai T, Uchida S, Sasaki S
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Journal Title
Intern Med
Volume: 49
Pages: 837-840
NAID
Related Report
Peer Reviewed
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