2011 Fiscal Year Final Research Report
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 |
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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 |
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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| Keywords | 水電解質 |
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| 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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[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
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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
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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
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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
PLoS One
Volume: 6(8)
Pages: e24277
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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)
Pages: F297-307
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