title: Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice.
abstract: 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 SpakT243A/+ and Osr1T185A/+ 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.
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Nishida
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nomura
authors.forename: Motoko
authors.initials: M
authors.lastname: Chiga
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.forename: Tatemitsu
authors.initials: T
authors.lastname: Rai
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D006946:Hyperinsulinism / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D015778:Minor Histocompatibility Antigens; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011955:Receptors, Drug; D049993:Sodium Chloride Symporter Inhibitors; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D000076204:WNK Lysine-Deficient Protein Kinase 1; C578875:Slc12a3 protein, mouse; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; C498744:Wnk1 protein, mouse