Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice

DOI Web Site PubMed 被引用文献29件 参考文献53件 オープンアクセス
  • Hidenori Nishida
    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.
  • Eisei Sohara
    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.
  • Naohiro Nomura
    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.
  • Motoko Chiga
    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.
  • Dario R. Alessi
    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.
  • Tatemitsu Rai
    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.
  • Sei Sasaki
    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.
  • Shinichi Uchida
    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.

書誌事項

公開日
2012-10
資源種別
journal article
DOI
  • 10.1161/hypertensionaha.112.201509
公開者
Ovid Technologies (Wolters Kluwer Health)

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説明

<jats:p> 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 <jats:sup>T243A/+</jats:sup> and Osr1 <jats:sup>T185A/+</jats:sup> 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. </jats:p>

収録刊行物

  • Hypertension

    Hypertension 60 (4), 981-990, 2012-10

    Ovid Technologies (Wolters Kluwer Health)

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