{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360846643661445248.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1161/hypertensionaha.112.201509"}},{"identifier":{"@type":"URI","@value":"https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.112.201509"}},{"identifier":{"@type":"PMID","@value":"22949526"}}],"resourceType":"学術雑誌論文(journal article)","dc:title":[{"@value":"Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:p>\n            Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) phosphorylation cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased phosphorylation of OSR1/SPAK and NCC was observed. In both Spak\n            <jats:sup>T243A/+</jats:sup>\n            and Osr1\n            <jats:sup>T185A/+</jats:sup>\n            knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, 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 in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.\n          </jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380003447007956097","@type":"Researcher","foaf:name":[{"@value":"Hidenori Nishida"}],"jpcoar:affiliationName":[{"@value":"From the Department of Nephrology (H.N., E.S., N.N., M.C., T.R., S.S., S.U.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Medical Research Council Protein Phosphorylation Unit (D.R.A.), College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom."}]},{"@id":"https://cir.nii.ac.jp/crid/1420001326226288256","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"90510355"},{"@type":"NRID","@value":"1000090510355"},{"@type":"NRID","@value":"9000259331327"},{"@type":"NRID","@value":"9000301749115"},{"@type":"NRID","@value":"9000411644016"},{"@type":"NRID","@value":"9000004018386"},{"@type":"NRID","@value":"9000345290628"},{"@type":"NRID","@value":"9000342797543"},{"@type":"NRID","@value":"9000405522075"},{"@type":"NRID","@value":"9000107386936"},{"@type":"NRID","@value":"9000292185661"},{"@type":"NRID","@value":"9000018697656"},{"@type":"NRID","@value":"9000347069260"},{"@type":"NRID","@value":"9000403048089"},{"@type":"NRID","@value":"9000402924094"},{"@type":"NRID","@value":"9000241523209"},{"@type":"NRID","@value":"9000410959908"},{"@type":"NRID","@value":"9000021842293"},{"@type":"NRID","@value":"9000399224819"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/read0099737"}],"foaf:name":[{"@value":"Eisei Sohara"}],"jpcoar:affiliationName":[{"@value":"From the Department of Nephrology (H.N., E.S., N.N., M.C., T.R., S.S., S.U.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Medical Research Council Protein Phosphorylation Unit (D.R.A.), College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom."}]},{"@id":"https://cir.nii.ac.jp/crid/1380003447007956096","@type":"Researcher","foaf:name":[{"@value":"Naohiro Nomura"}],"jpcoar:affiliationName":[{"@value":"From the Department of Nephrology (H.N., E.S., N.N., M.C., T.R., S.S., S.U.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Medical Research Council Protein Phosphorylation Unit (D.R.A.), College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom."}]},{"@id":"https://cir.nii.ac.jp/crid/1380003447007956098","@type":"Researcher","foaf:name":[{"@value":"Motoko Chiga"}],"jpcoar:affiliationName":[{"@value":"From the Department of Nephrology (H.N., E.S., N.N., M.C., T.R., S.S., S.U.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Medical Research Council Protein Phosphorylation Unit (D.R.A.), College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom."}]},{"@id":"https://cir.nii.ac.jp/crid/1380003447007956101","@type":"Researcher","foaf:name":[{"@value":"Dario R. Alessi"}],"jpcoar:affiliationName":[{"@value":"From the Department of Nephrology (H.N., E.S., N.N., M.C., T.R., S.S., S.U.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Medical Research Council Protein Phosphorylation Unit (D.R.A.), College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom."}]},{"@id":"https://cir.nii.ac.jp/crid/1420564276178263552","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"80334431"},{"@type":"NRID","@value":"1000080334431"},{"@type":"NRID","@value":"9000345290629"},{"@type":"NRID","@value":"9000363331647"},{"@type":"NRID","@value":"9000406216931"},{"@type":"NRID","@value":"9000414828462"},{"@type":"NRID","@value":"9000292185663"},{"@type":"NRID","@value":"9000406283965"},{"@type":"NRID","@value":"9000347069261"},{"@type":"NRID","@value":"9000314382911"},{"@type":"NRID","@value":"9000256092554"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/read0098860"}],"foaf:name":[{"@value":"Tatemitsu Rai"}],"jpcoar:affiliationName":[{"@value":"From the Department of Nephrology (H.N., E.S., N.N., M.C., T.R., S.S., S.U.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Medical Research Council Protein Phosphorylation Unit (D.R.A.), College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom."}]},{"@id":"https://cir.nii.ac.jp/crid/1380003447007956103","@type":"Researcher","foaf:name":[{"@value":"Sei Sasaki"}],"jpcoar:affiliationName":[{"@value":"From the Department of Nephrology (H.N., E.S., N.N., M.C., T.R., S.S., S.U.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Medical Research Council Protein Phosphorylation Unit (D.R.A.), College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom."}]},{"@id":"https://cir.nii.ac.jp/crid/1420001326210303104","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"50262184"},{"@type":"NRID","@value":"1000050262184"},{"@type":"NRID","@value":"9000347068990"},{"@type":"NRID","@value":"9000363360519"},{"@type":"NRID","@value":"9000410890543"},{"@type":"NRID","@value":"9000292867748"},{"@type":"NRID","@value":"9000283529535"},{"@type":"NRID","@value":"9000021457467"},{"@type":"NRID","@value":"9000007593863"},{"@type":"NRID","@value":"9000363360442"},{"@type":"NRID","@value":"9000347068925"},{"@type":"NRID","@value":"9000400159525"},{"@type":"NRID","@value":"9000018852129"},{"@type":"NRID","@value":"9000409795921"},{"@type":"NRID","@value":"9000020064467"},{"@type":"NRID","@value":"9000344116637"},{"@type":"NRID","@value":"9000389003127"},{"@type":"NRID","@value":"9000004031453"},{"@type":"NRID","@value":"9000397656913"},{"@type":"NRID","@value":"9000018388665"},{"@type":"NRID","@value":"9000018970047"},{"@type":"NRID","@value":"9000347071760"},{"@type":"NRID","@value":"9000254505092"},{"@type":"NRID","@value":"9000378057888"},{"@type":"NRID","@value":"9000391922401"},{"@type":"NRID","@value":"9000258029221"},{"@type":"NRID","@value":"9000009637458"},{"@type":"NRID","@value":"9000403030078"},{"@type":"NRID","@value":"9000347069259"},{"@type":"NRID","@value":"9000347066100"},{"@type":"NRID","@value":"9000010716887"},{"@type":"NRID","@value":"9000331470678"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/read0180677"}],"foaf:name":[{"@value":"Shinichi Uchida"}],"jpcoar:affiliationName":[{"@value":"From the Department of Nephrology (H.N., E.S., N.N., M.C., T.R., S.S., S.U.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Medical Research Council Protein Phosphorylation Unit (D.R.A.), College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom."}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"0194911X"},{"@type":"EISSN","@value":"15244563"},{"@type":"PISSN","@value":"http://id.crossref.org/issn/0194911X"}],"prism:publicationName":[{"@value":"Hypertension"}],"dc:publisher":[{"@value":"Ovid Technologies (Wolters Kluwer Health)"}],"prism:publicationDate":"2012-10","prism:volume":"60","prism:number":"4","prism:startingPage":"981","prism:endingPage":"990"},"reviewed":"false","dcterms:accessRights":"http://purl.org/coar/access_right/c_abf2","url":[{"@id":"https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.112.201509"}],"createdAt":"2012-09-05","modifiedAt":"2024-05-13","foaf:topic":[{"@id":"https://cir.nii.ac.jp/all?q=Symporters","dc:title":"Symporters"},{"@id":"https://cir.nii.ac.jp/all?q=Receptors,%20Drug","dc:title":"Receptors, Drug"},{"@id":"https://cir.nii.ac.jp/all?q=Sodium%20Chloride%20Symporter%20Inhibitors","dc:title":"Sodium Chloride Symporter Inhibitors"},{"@id":"https://cir.nii.ac.jp/all?q=Blood%20Pressure","dc:title":"Blood Pressure"},{"@id":"https://cir.nii.ac.jp/all?q=Protein%20Serine-Threonine%20Kinases","dc:title":"Protein Serine-Threonine Kinases"},{"@id":"https://cir.nii.ac.jp/all?q=Kidney","dc:title":"Kidney"},{"@id":"https://cir.nii.ac.jp/all?q=Minor%20Histocompatibility%20Antigens","dc:title":"Minor Histocompatibility Antigens"},{"@id":"https://cir.nii.ac.jp/all?q=Mice","dc:title":"Mice"},{"@id":"https://cir.nii.ac.jp/all?q=Phosphatidylinositol%203-Kinases","dc:title":"Phosphatidylinositol 3-Kinases"},{"@id":"https://cir.nii.ac.jp/all?q=WNK%20Lysine-Deficient%20Protein%20Kinase%201","dc:title":"WNK Lysine-Deficient Protein Kinase 1"},{"@id":"https://cir.nii.ac.jp/all?q=Hyperinsulinism","dc:title":"Hyperinsulinism"},{"@id":"https://cir.nii.ac.jp/all?q=Animals","dc:title":"Animals"},{"@id":"https://cir.nii.ac.jp/all?q=Solute%20Carrier%20Family%2012,%20Member%203","dc:title":"Solute Carrier Family 12, Member 3"},{"@id":"https://cir.nii.ac.jp/all?q=Phosphorylation","dc:title":"Phosphorylation"},{"@id":"https://cir.nii.ac.jp/all?q=Proto-Oncogene%20Proteins%20c-akt","dc:title":"Proto-Oncogene Proteins c-akt"},{"@id":"https://cir.nii.ac.jp/all?q=Signal%20Transduction","dc:title":"Signal Transduction"}],"project":[{"@id":"https://cir.nii.ac.jp/crid/1040000782031172736","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"20249047"},{"@type":"JGN","@value":"JP20249047"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20249047/"}],"notation":[{"@language":"ja","@value":"腎臓膜輸送体を制御する新規細胞内刺激伝達系の解明"},{"@language":"en","@value":"A novel WNK signal cascade regulating renal transporters"}]},{"@id":"https://cir.nii.ac.jp/crid/1040000782106124800","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"22249032"},{"@type":"JGN","@value":"JP22249032"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22249032/"}],"notation":[{"@language":"ja","@value":"新たな腎臓膜輸送体制御法の開発"},{"@language":"en","@value":"Novel strategy to regulate renal channels and transporters"}]},{"@id":"https://cir.nii.ac.jp/crid/1040000782112581888","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"22390168"},{"@type":"JGN","@value":"JP22390168"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22390168/"}],"notation":[{"@language":"ja","@value":"腎臓における新規の血圧調節機構ＷＮＫ－ＮＣＣシグナル伝達系の解明"},{"@language":"en","@value":"Analysis of WNK-NCC signaling cascade, a novel blood pressure controlling system, in the kidney"}]},{"@id":"https://cir.nii.ac.jp/crid/1040000782176789376","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"23659439"},{"@type":"JGN","@value":"JP23659439"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659439/"}],"notation":[{"@language":"ja","@value":"蛋白相互作用阻害によるWNKキナーゼ阻害薬の効率的スクリーニング"},{"@language":"en","@value":"Efficient chemical library screening for WNK signaling inhibitors byinhibiting WNK-SPAK interaction"}]},{"@id":"https://cir.nii.ac.jp/crid/1040282257199540864","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"24659413"},{"@type":"JGN","@value":"JP24659413"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24659413/"}],"notation":[{"@language":"ja","@value":"小胞体水チャネルの病態生理学的役割の解明"},{"@language":"en","@value":"Role of aquaporins in endoplasmic reticulum"}]},{"@id":"https://cir.nii.ac.jp/crid/1040282257207177344","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"24790836"},{"@type":"JGN","@value":"JP24790836"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24790836/"}],"notation":[{"@language":"ja","@value":"インスリンと塩分感受性高血圧をつなぐＷＮＫキナーゼ"},{"@language":"en","@value":"WNK kinase links insulin with salt-sensitive hypertension"}]}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360002215822810752","@type":"Article","resourceType":"学術雑誌論文(journal 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regulates Na\n            <sup>+</sup>\n            channel and K\n            <sup>+</sup>\n            channel activity and has implications for aldosterone signaling and K\n            <sup>+</sup>\n            homeostasis"}]},{"@id":"https://cir.nii.ac.jp/crid/1360011144794838528","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Phenotypic And Genetic Heterogeneity Of Familial Hyperkalaemic Hypertension (Gordon Syndrome)"}]},{"@id":"https://cir.nii.ac.jp/crid/1360011145238142208","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"<i>N</i>-Acetyl-Seryl-Aspartyl-Lysyl-Proline Prevents Renal Insufficiency and Mesangial Matrix Expansion in Diabetic <i>db/db</i> Mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1360011146031884416","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted Drugs\n                    <i>In vitro</i>\n                    and\n                    <i>In vivo</i>"}]},{"@id":"https://cir.nii.ac.jp/crid/1360013168739031680","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Structural Development of Salicylanilide‐Based SPAK Inhibitors as Candidate Antihypertensive Agents"}]},{"@id":"https://cir.nii.ac.jp/crid/1360021390753760768","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Kamishoyosan and Kamikihito protect against decreased KCC2 expression induced by the P. gingivalis lipopolysaccharide treatment in PC-12 cells and improve behavioral abnormalities in male mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285706978151552","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285707079863040","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"WNK4 is an Adipogenic Factor and Its Deletion Reduces Diet-Induced Obesity in Mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285711412868352","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Dietary Salt Intake Regulates WNK3–SPAK–NKCC1 Phosphorylation Cascade in Mouse Aorta Through Angiotensin II"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285713114919808","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters"}]},{"@id":"https://cir.nii.ac.jp/crid/1360286993324579200","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"The WNK signaling pathway and salt-sensitive hypertension"}]},{"@id":"https://cir.nii.ac.jp/crid/1360290617862663424","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK inhibitors blocking WNK kinase signaling"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292619969899520","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292620234915200","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Insulin sensitivity and the effects of insulin on renal sodium handling and pressor systems in essential hypertensive 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