Elucidation of the molecular pathogenesis of sarcopenia and development of novel therapeutic strategies

2023 Fiscal Year Final Research Report

• Project/Area Number: 19H03556
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Dokkyo Medical University (2022-2023); Tokyo Medical and Dental University (2019-2021)
• Principal Investigator: Rai Tatemitsu 獨協医科大学, 医学部, 教授 (80334431)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: WNKキナーゼ

Outline of Final Research Achievements

As for novel function of the WNK signalling system, this system was found to be involved in the pathogenesis of increased salt sensitivity in chronic kidney disease (CKD) via TNFα. A novel regulatory mechanism of Na-Cl co-transporters in urinary potassium excretion was also revealed.
Regarding the molecular mechanism of abnormal energy metabolism in CKD, we found that there is an AMPK-mediated energy-deficiency sensing defect and that AMPK activation in an AMP-independent manner may be a novel therapy to ameliorate CKD.
Furthermore, a clinical study of a large cohort of patients with CKD showed that a reduction in patients' functional status on admission significantly increased in-hospital mortality, length of stay and costs.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

マウスCKDモデルを用いて、CKDにおける塩分感受性亢進のメカニズムの一端を解明、WNKキナーゼとTNFαがCKDにおける塩分感受性亢進と免疫機構を繋ぐ鍵分子であることを初めて示すことに成功した。このようにWNKシグナルの新規機能を明らかにすることができた。
また、CKDにおけるエネルギー代謝異常の分子機構については、AMPKを介したエネルギー不全感知障害が存在することを明らかにし、CKDにおけるサルコペニア発症に繋がるエネルギー代謝障害についての新たな知見を得ることができたと同時に、AMPK活性化によるCKDの新規治療法の可能性についても見出すことができた。