Relationship between WNK kinase and hypertension in polycystic kidney disease

WNK激酶与多囊肾病高血压的关系

• 批准号: 20890062
• 负责人: SOHARA Eisei
• 金额: $ 2.11万
• 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 (Start-up)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20890062/
• 关键词: 塩分感受性高血圧; インスリン; NaCl共輸送体; WNKキナーゼ; 高血圧; 多発性嚢胞腎

The metabolic syndrome causes hyperinsulinemia and enhances salt-sensitive hypertension. However, the mechanisms responsible for the greater salt-sensitivity in hyperinsulinemic patients are still unknown. Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disease characterized by salt-sensitive hypertension due to increased sodium reabsorption in the kidney through activation of the WNK kinase-OSR1/SPAK kinase-NaCl cotransporter (NCC) phosphorylation cascade, which we recently discovered. We found that a PHAII-causing mutant WNK4 (WNK4 R1185C) abnormally increased phosphorylation of WNK4 at serine 1190, which resulted in activation of the downstream OSR1/SPAK-NCC phosphorylation cascade. Furthermore, we clarified that insulin is a powerful stimulator for WNK4 1190S phosphorylation, thereby activating the WNK-OSR1/SPAK-NCC cascade in vitro and in vivo. Thus, our results clearly show that a hyperinsulinemic condition causes salt-sensitive hypertension by the same mechanism as identified in PHAII. However, we could not find the significant relationship between PKD and WNK kinase.

代谢综合征引起高胰岛素血症并增强盐敏感性高血压。然而，高胰岛素血症患者盐敏感性更高的机制仍不清楚。假性醛固酮减少症II型（PHAII）是一种常染色体显性遗传疾病，其特征是盐敏感性高血压，这是由于我们最近发现的WNK激酶-OSR 1/SPAK激酶-NaCl协同转运蛋白（NCC）磷酸化级联反应激活导致肾脏钠重吸收增加所致。我们发现，一个PHAII引起的突变体WNK 4（WNK 4 R1185 C）异常增加WNK 4在丝氨酸1190处的磷酸化，这导致下游OSR 1/SPAK-NCC磷酸化级联反应的激活。此外，我们阐明了胰岛素是WNK 4 1190 S磷酸化的强有力刺激剂，从而在体外和体内激活WNK-OSR 1/SPAK-NCC级联反应。因此，我们的研究结果清楚地表明，高胰岛素血症引起盐敏感性高血压的机制与PHAII相同。然而，我们没有发现PKD和WNK激酶之间的显著关系。

项目成果

Novel insulin-WNK4-NCC phosphorylation cascade is involved in pathogenesis of PHA II caused by WNK4R1185C mutation

新型胰岛素-WNK4-NCC磷酸化级联参与WNK4R1185C突变引起的PHA II发病机制

• 发表时间: 2009
• 作者: Sohara E;Rai T;Ohta A;Ohta E;Sasaki S and Uchida S
• 通讯作者: Sasaki S and Uchida S

新規Insuhn-WNK4-NCCリン酸化カスケードの発見と偽性低アルドステロン症II型における破綻

发现新型 Insuhn-WNK4-NCC 磷酸化级联并破坏 II 型假性醛固酮增多症

• 发表时间: 2009
• 作者: 蘇原映誠;太田哲人;太田英里子;頼建光;内田信一;佐々木成
• 通讯作者: 佐々木成

嚢胞性腎疾患とNek8(NIMA-related kinase 8)

囊性肾病和 Nek8（NIMA 相关激酶 8）

• 发表时间: 2009
• 期刊: 腎と透析 67
• 作者: Yui N;Okutsu R;Sohara E;Rai T;Ohta A;Noda Y;Sasaki S;Uchida S.;石村瞳;阿部成宏;蘇原映誠
• 通讯作者: 蘇原映誠

Generation of liver specific Pkd1 knockout mice

肝脏特异性 Pkd1 敲除小鼠的产生

• 发表时间: 2008
• 作者: Eisei Sohara;Funda Saglam;Jingjing Zhang;Leah Contrino;Alexander Beck;Jing Zhou
• 通讯作者: Jing Zhou

Pancreas-specific aquaporin 12 null mice showed increased susceptibility to caerulein-induced acute pancreatitis

• DOI: 10.1152/ajpcell.00117.2009
• 发表时间: 2009-12-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
• 影响因子: 5.5
• 作者: Ohta, Eriko;Itoh, Tomohiro;Rai, Tatemitsu
• 通讯作者: Rai, Tatemitsu