Elucidation of the pathogenesis of salt-sensitive hypertension in chronic kidney disease caused by inflammation

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17276
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Hashimoto Hiroko 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (60846062)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 慢性腎臓病 / 塩分感受性 / WNK / 炎症

Outline of Final Research Achievements

Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of the WNK phosphorylation cascade is unknown. Here we demonstrate that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules in the aristolochic acid nephropathy mouse model of CKD. We hypothesized that tumor necrosis factor (TNF)-a regulates WNK1 protein expression. In fact, TNF-a increased WNK1 protein expression in cultured renal tubular cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNF-a inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of the WNK1 cascade in distal convoluted tubules in vivo in CKD model. Thus, salt-sensitive hypertension is induced in CKD via activation of the renal WNK signal by TNF-a, reflecting a link with the immune system.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、WNK シグナルが免疫機構による血圧制御メカニズムの一端を担っており、CKD の塩分感受性亢 進に関わっていることを世界に先駆けて明らかにした。CKDではNCCの阻害薬であるサイアザイド系利尿薬の効果に個人差があることが知られており、サイアザイドの有効なCKDでTNFα-WNK1-SPAK-NCC シグナルが活性化している可能性が示唆された。そのため、腎臓でのTNFα産生の評価は腎機能の低下した患者個々に対する適切な降圧療法選択に有用と考えられた。