WNK kinase links insulin with salt-sensitive hypertension

WNK 激酶将胰岛素与盐敏感性高血压联系起来

• 批准号: 24790836
• 负责人: SOHARA EISEI
• 金额: $ 2.66万
• 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: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24790836/
• 关键词: インスリン; メタボリック症候群; 塩分感受性高血圧; WNKキナーゼ; サイアザイド; 水・電解質代謝学; 肥満; WNKシグナル; WNK; NCC; 高血圧

We found renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. In SPAK/OSR1 knock-in db/db mice, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC. Moreover, we found that Increased NCC phosphorylation is regulated by the PI3K/Akt signaling cascade in the kidney in response to hyperinsulinemia. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome. We also found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 mutation, due to impaired KLHL3-Cullin3 mediated ubiquitination.

我们在高胰岛素代谢综合征的db/db小鼠模型中发现肾脏WNK-OSR1/SPAK-NCC级联激活。在SPAK/OSR1敲入db/db小鼠中，NCC磷酸化升高和血压升高被完全纠正，这表明WNK激酶对SPAK和OSR1的磷酸化是NCC活化和磷酸化增加所必需的。此外，我们发现NCC磷酸化的增加在高胰岛素血症时受到肾脏PI3K/Akt信号级联的调节。这一机制可能在人类高胰岛素血症如代谢综合征的盐敏感性高血压发病机制中发挥作用。我们还发现，由于KLHL3- cullin3介导的泛素化受损，WNK1和WNK4激酶的蛋白表达水平升高导致KLHL3突变导致PHAII。

项目成果

WNK3 regulates blood pressure through the regulation of vascular OSR1 / SPAK-NKCC1 phosphorylation cascade

WNK3通过调节血管OSR1/SPAK-NKCC1磷酸化级联来调节血压

• 发表时间: 2013
• 作者: Zeniya M;Sohara E;Oi K;Chiga M;Susa K;Mori T;Takahashi D;Rai T;Sasaki S;Uchida S
• 通讯作者: Uchida S

Does a β2-adrenergic receptor-WNK4-Na-Cl co-transporter signal cascade exist in the in vivo kidney?

体内肾脏中是否存在β2-肾上腺素受体-WNK4-Na-Cl协同转运蛋白信号级联？

• DOI: 10.1038/nm.2809
• 发表时间: 2012
• 期刊: Nat. Med.
• 作者: Aoki T.;他;Hara-Chikuma M;Hossain Khan MZ;Iimori S;Iimori S;Kanda E;Magdeldin S;Mandai S;Nishida H;Ohtaki H;Oi K;Sasaki S.;Susa K;Susa K;Uchida S
• 通讯作者: Uchida S

Investigation of Pathophysiology of Renal Sodium and Water Transport Disorders

肾脏钠和水转运障碍的病理生理学研究

• 发表时间: 2013
• 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

Low salt intake decreased transcription and protein level of KLHL3 in mouse kidney

低盐摄入量降低了小鼠肾脏中 KLHL3 的转录和蛋白水平

• 发表时间: 2013
• 作者: Susa K;Sohara E;Zeniya M;Rai T;Sasaki S;Uchida S.
• 通讯作者: Uchida S.