WNK kinase links salt-sensitive hypertension with obesity

WNK 激酶将盐敏感性高血压与肥胖联系起来

• 批准号: 22790783
• 负责人: SOHARA Eisei
• 金额: $ 2.5万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790783/
• 关键词: 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

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.

氯化钠协同转运蛋白（NCC）对于远曲小管（DCT）的钠重吸收至关重要，其磷酸化增加了其转运活性和顶膜定位。尽管据报道胰岛素可以增加肾脏对钠的重吸收，但胰岛素与 NCC 磷酸化之间的联系尚未得到研究。本研究检验了胰岛素是否调节 NCC 磷酸化。在培养的 mpkDCT 细胞中，胰岛素以剂量依赖性方式增加 STE20/SPS1 相关的富含脯氨酸丙氨酸激酶 (SPAK) 和 NCC 的磷酸化。这种胰岛素诱导的 NCC 磷酸化在 WNK4 和 SPAK 敲低细胞中受到抑制。此外，PI3K抑制剂Ly294002降低了胰岛素对SPAK和NCC磷酸化的作用，表明胰岛素通过PI3K和WNK4在mpkDCT细胞中诱导SPAK和NCC磷酸化。此外，对小鼠进行急性胰岛素注射会增加肾脏中氧化应激反应激酶1（OSR1）、SPAK和NCC的磷酸化。 mpkDCT细胞和小鼠的时程实验表明，在胰岛素诱导的NCC磷酸化机制中，SPAK是NCC的上游，SPAK敲除小鼠中缺乏胰岛素诱导的NCC磷酸化也证实了这一点。此外，给WNK4低效型小鼠注射胰岛素并没有增加肾脏中OSR1、SPAK和NCC的磷酸化，表明WNK4也参与了胰岛素诱导的体内OSR1、SPAK和NCC磷酸化机制。目前的结果表明，胰岛素是肾脏中 NCC 磷酸化的有效调节剂，并且 WNK4 和 SPAK 参与了胰岛素对 NCC 磷酸化的这种机制。

项目成果

偽性低アルドステロン症II型

II型假性醛固酮增多症

• 作者: Inaba S;Nagahara S;Makita N;Tarumi Y;Ishimoto T;Matsuo S;Kadomatsu K;Takei Y.;森崇寧,内田信一
• 通讯作者: 森崇寧,内田信一

WNKキナーゼ遺伝子改変マウスによるNa-Cl共輸送体制御機構の解明

利用 WNK 激酶基因修饰小鼠阐明 Na-Cl 协同转运蛋白的调节机制

• 发表时间: 2011
• 作者: Chiang CK;Tanaka T;蘇原映誠
• 通讯作者: 蘇原映誠

Severe hyperparathyroidism in a pre-dialysis chronic kidney disease patient treated with a very low protein diet

接受极低蛋白质饮食治疗的透析前慢性肾病患者出现严重甲状旁腺功能亢进

• DOI: 10.1007/s00774-011-0320-6
• 发表时间: 2011
• 期刊: J. Bone Miner. Metab.
• 作者: Asano;H.;Horinouchi;T.;Mai;Y.;Sawada;O.;Fujii;S.;Nishiya;T.,;星暁壮，堀之内孝広，原田拓弥，比嘉綱己，東恒仁，寺田晃士，眞井洋輔，ネパル・プラハ，堀口美香，旗手千鶴，三輪聡一;Ohta E
• 通讯作者: Ohta E

インスリンと塩分感受性高血圧症をつなぐ新規インスリン-WNK4-NCCリン酸化カスケードの発見

发现一种连接胰岛素和盐敏感性高血压的新型胰岛素-WNK4-NCC磷酸化级联

• 发表时间: 2010
• 作者: Sohara E;Rai T;Yang SS;Ohta A;ChigaM;Nomura N;Lin SH;Vandewalle A;SasakiS;Uchida S.;Tanaka T;蘇原映誠
• 通讯作者: 蘇原映誠

Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade

• DOI: 10.1242/jcs.084111
• 发表时间: 2011-05-01
• 期刊: JOURNAL OF CELL SCIENCE
• 影响因子: 4
• 作者: Chiga, Motoko;Rafiqi, Fatema H.;Uchida, Shinichi
• 通讯作者: Uchida, Shinichi