2022 Fiscal Year Final Research Report

Intra-renal signaling through post-translational modification as the potential target to counteract kidney diseases

Research Project

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Project/Area Number	19H03678
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 53040:Nephrology-related
Research Institution	Teikyo University
Principal Investigator	Shibata Shigeru 帝京大学, 医学部, 教授 (60508068)
Co-Investigator(Kenkyū-buntansha)	田村好古帝京大学, 医学部, 講師 (10459315) 石澤健一帝京大学, 医学部, 講師 (10772684) 山崎修帝京大学, 医学部, 講師 (80757229)
Project Period (FY)	2019-04-01 – 2023-03-31
Keywords	体液恒常性 / 膜輸送体 / 翻訳後修飾
Outline of Final Research Achievements	The study aimed to reveal pathological significance of membrane transport regulatory mechanisms involving post-translational modification.1. In obese diabetic mice, we found that aberrant phosphorylation of KLHL3 increases salt sensitivity by promoting salt reabsorption in the distal tubules. These abnormalities were corrected by SGLT2 inhibition, suggesting the functional interaction between proximal and distal tubules (JASN 2019). This mechanism is also involved in the electrolyte abnormalities associated with calcineurin inhibitors (PNAS 2019). 2. We found that disturbed phosphorus metabolism is involved in the pathophysiology of salt-sensitive hypertension and salt-induced kidney injury in Dahl rats, which is associated with the alteration in klotho and Na-Pi transporters (Commun Biol 2020). 3.Using urinary extracellular vesicle fraction, we demonstrated the involvement of the blood pressure regulatory molecule pendrin in secondary hypertension in humans (Hypertens Res 2021).
Free Research Field	腎臓内科学
Academic Significance and Societal Importance of the Research Achievements	腎尿細管による体液恒常性維持機構は陸生脊椎動物の長い年月をかけた進化の過程で発達してきたものと考えられるが、このような精巧な体液保持システムが仇となり、人類の急速な食生活習慣の変化に伴って表出しているのが生活習慣病である。本研究の成果により生活習慣病と密接に関連する食塩のハンドリング異常、ならびにその結果として惹起される体内での食塩過剰が臓器障害を加速させる分子メカニズムの一端が明らかとなり、生活習慣病の予防や管理改善に向けて有用な知見が得られたものと考えられる。