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

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 iden...

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Veröffentlicht in:Hypertension (Dallas, Tex. 1979) Tex. 1979), 2012-10, Vol.60 (4), p.981-990
Hauptverfasser: Nishida, Hidenori, Sohara, Eisei, Nomura, Naohiro, Chiga, Motoko, Alessi, Dario R, Rai, Tatemitsu, Sasaki, Sei, Uchida, Shinichi
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container_issue 4
container_start_page 981
container_title Hypertension (Dallas, Tex. 1979)
container_volume 60
creator Nishida, Hidenori
Sohara, Eisei
Nomura, Naohiro
Chiga, Motoko
Alessi, Dario R
Rai, Tatemitsu
Sasaki, Sei
Uchida, Shinichi
description 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 and Osr1 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.
doi_str_mv 10.1161/HYPERTENSIONAHA.112.201509
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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 and Osr1 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. 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Etiology</subject><subject>Hyperinsulinism - metabolism</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kidney - physiopathology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Minor Histocompatibility Antigens</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation - drug effects</subject><subject>Phosphorylation - physiology</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Receptors, Drug - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Sodium Chloride Symporter Inhibitors - pharmacology</subject><subject>Solute Carrier Family 12, Member 3</subject><subject>Symporters - metabolism</subject><subject>WNK Lysine-Deficient Protein Kinase 1</subject><issn>0194-911X</issn><issn>1524-4563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkd2O0zAQhS0EYsvCKyALCYmbbD3OT2MukKKq0FWXttpWAq4ix3Y2Zt2k2A5VXoGnxksKSFxxNdLMN2eO5iD0CsgVQAbT5Zft4na_WO-uN-tiWYQmvaIEUsIeoQmkNImSNIsfowkBlkQM4PMFeubcV0IgSZLZU3RBKUtYSrMJ-rFtOndsuNdyMLrtnPadwXG00i13alrce7zTdy0Pszu85b458QEXwuvv3CuHfaPwp_Uq2uxuYbrbFqtoPZ_jUbOzgwm6XYvn3AkuFdYtXg5HZXXr-iCoDlpgWU1lhT9qoZ6jJzU3Tr0410u0f7_Yz5fRzebD9by4iUQafEeKckVgJoHlsmZc5oLmGRAGFcsBVFXVdRwDrVkss0zmlWCC5VmcCy4o5yS-RG9G2aPtvvXK-fKgnVDG8FZ1vSuBxCzP0zSBgL4dUWE756yqy6PVB26HAJUPUZT_RBGatByjCMsvz3f66qDkn9Xfvw_A6zPw8B5TW94K7f5yWZxks18u3o3cqTNeWXdv-pOyZaO48c3_OPkJB2iolQ</recordid><startdate>201210</startdate><enddate>201210</enddate><creator>Nishida, Hidenori</creator><creator>Sohara, Eisei</creator><creator>Nomura, Naohiro</creator><creator>Chiga, Motoko</creator><creator>Alessi, Dario R</creator><creator>Rai, Tatemitsu</creator><creator>Sasaki, Sei</creator><creator>Uchida, Shinichi</creator><general>American Heart Association, Inc</general><general>Lippincott Williams &amp; Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201210</creationdate><title>Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice</title><author>Nishida, Hidenori ; Sohara, Eisei ; Nomura, Naohiro ; Chiga, Motoko ; Alessi, Dario R ; Rai, Tatemitsu ; Sasaki, Sei ; Uchida, Shinichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5229-e2ae017d198df9ad8c2861091b9811ebbff3312f93d66d8bc9c98638cac2aa03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Arterial hypertension. 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This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>22949526</pmid><doi>10.1161/HYPERTENSIONAHA.112.201509</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete
subjects Animals
Arterial hypertension. Arterial hypotension
Biological and medical sciences
Blood and lymphatic vessels
Blood Pressure - physiology
Cardiology. Vascular system
Clinical manifestations. Epidemiology. Investigative techniques. Etiology
Hyperinsulinism - metabolism
Kidney - drug effects
Kidney - metabolism
Kidney - physiopathology
Medical sciences
Mice
Minor Histocompatibility Antigens
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation - drug effects
Phosphorylation - physiology
Protein Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Receptors, Drug - metabolism
Signal Transduction - drug effects
Signal Transduction - physiology
Sodium Chloride Symporter Inhibitors - pharmacology
Solute Carrier Family 12, Member 3
Symporters - metabolism
WNK Lysine-Deficient Protein Kinase 1
title Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice
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