Relationship between WNK kinase and hypertension in polycystic kidney disease

2009 Fiscal Year Final Research Report

• Project/Area Number: 20890062
• Research Category: Grant-in-Aid for Young Scientists (Start-up)
• Allocation Type: Single-year Grants
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: SOHARA Eisei Tokyo Medical and Dental University, 医歯学総合研究科, 助教 (90510355)
• Project Period (FY): 2008 – 2009
• Keywords: 塩分感受性高血圧 / インスリン / NaCl共輸送体 / WNKキナーゼ

Research Abstract

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.

Research Products

• [Journal Article] Calcium-alkali syndrome-like symptoms manifested by daily alphacalcidol and thiazide (2010)
  • Author(s): Satoh F, Okado T, Iwamoto M, Akita W, Wakabayashi M, Ohta A, Sohara E, Noda Y, Rai T, Uchida S, Sasaki S.
  • Journal Title: Intern Med. 49(9) Pages: 837-40
• [Journal Article] Effect of angiotensin II on the WNK-OSR1/SPAK-NCC phosphorylation cascade in cultured mpkDCT cells and in vivo mouse kidney (2010)
  • Author(s): Talati G, Ohta A, Rai T, Sohara E, Naito S, Vandewalle A, Sasaki S, Uchida S.
  • Journal Title: Biochem Biophys Res Commun. 393(4) Pages: 844-8
• [Journal Article] Aquaporins in kidney pathophysiology (2010)
  • Author(s): Noda Y, Sohara E, Ohta E, Sasaki S.
  • Journal Title: Nat Rev Nephrol. 6(3) Pages: 168-78
• [Journal Article] FAPP2 is required for aquaporin-2 apical sorting at trans-Golgi network in polarized MDCK cells (2009)
  • Author(s): Yui N, Okutsu R, Sohara E, Rai T, Ohta A, Noda Y, Sasaki S, Uchida S.
  • Journal Title: Am J Physiol Cell Physiol. 297(6) Pages: C1389-96
• [Journal Article] Pancreas-specific aquaporin 12 null mice showed increased susceptibility to caerulein-induced acute pancreatitis (2009)
  • Author(s): Ohta E, Itoh T, Nemoto T, Kumagai J, Ko SB, Ishibashi K, Ohno M, Uchida K, Ohta A, Sohara E, Uchida S, Sasaki S, Rai T.
  • Journal Title: Am J Physiol Cell Physiol. 297(6) Pages: C1368-78
• [Journal Article] Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure (2009)
  • Author(s): Ohta A, Rai T, Yui N, Chiga M, Yang SS, Lin SH, Sohara E, Sasaki S, Uchida S.
  • Journal Title: Hum Mol Genet. 18(20) Pages: 3978-86
• [Presentation] Novel insulin-WNK4-NCC phosphorylation cascade is involved in pathogenesis of PHA II caused by WNK4 R1185C mutation (2009)
  • Author(s): Sohara E, Rai T, Ohta A, Ohta E, Sasaki S, Uchida S.
  • Organizer: The 42nd Annual Meeting of American Society of Nephrology
  • Place of Presentation: San Diego
  • Year and Date: 20091100
• [Presentation] 新規 Insulin-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 (2009)
  • Author(s): 蘇原映誠, 太田哲人, 太田英里子, 頼建光, 内田信一, 佐々木成
  • Organizer: 第15回分子腎臓研究会
  • Place of Presentation: 京都
  • Year and Date: 20090900
• [Presentation] Generation of liver specific Pkd1 knockout mice (2008)
  • Author(s): Eisei Sohara, Funda Saglam, Jingjing Zhang, Leah Contrino, Alexander Beck, Jing Zhou
  • Organizer: The 41st Annual meeting of American Society of Nephrology 7th
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 20081100
• [Presentation] Nek8 (NIMA-related kinase 8) と嚢胞性腎疾患 (2008)
  • Author(s): 蘇原映誠
  • Organizer: 第94回 東京腎生理集団会
  • Place of Presentation: 東京
  • Year and Date: 20081100
• [Presentation] Nek8 (NIMA-related kinase 8) と嚢胞性腎疾患 (2008)
  • Author(s): 蘇原映誠
  • Organizer: 生理研研究会
  • Place of Presentation: 愛知
  • Year and Date: 20080700
• [Book] Handb Exp Pharmacol. (2009)
  • Author(s): Sohara E, Uchida S, Sasaki S.
  • Total Pages: 219-31