2020 Fiscal Year Final Research Report

Regulation of nuclear receptor through autophagy-related proteins and other mechanisms

Research Project

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Project/Area Number	19K22643
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
Research Institution	Teikyo University
Principal Investigator	Shibata Shigeru 帝京大学, 医学部, 教授 (60508068)
Co-Investigator(Kenkyū-buntansha)	岡崎具樹帝京大学, 医学部, 教授 (60203973) 藤垣嘉秀帝京大学, 医学部, 教授 (20283351) 石澤健一帝京大学, 医学部, 講師 (10772684) 諏佐崇生帝京大学, 医学部, 助教 (20445852)
Project Period (FY)	2019-06-28 – 2021-03-31
Keywords	ミネラルコルチコイド受容体 / pendrin / 食塩感受性 / ビタミンD受容体
Outline of Final Research Achievements	MR modulates the activity of transporters and channels in the kidney, regulating fluid homeostasis. We previously reported that pendrin, a Cl/HCO3 exchanger, plays a key role in determining the balance between salt reabsorption and potassium excretion, and also showed that dephosphorylation of MR at the ligand-binding domain by the inactivation of ULK1 through AngII signaling increases pendrin, maximizing salt reabsorption. Using extracellular vesicles (EVs) isolated from urine, we determined the clinical significance of primary aldosteronism (PA), a major form of secondary hypertension. Pendrin in urinary EVs was highly correlated with renal expression, and its abundance was significantly attenuated by therapeutic interventions in PA. As a mechanism that regulates vitamin D receptor (VDR), another nuclear receptor highly present in the renal distal nephron, we showed that 25D3 can stimulate VDR target genes, uncovering an alternative regulation of VDR signaling in renal tubules.
Free Research Field	腎臓内科学
Academic Significance and Societal Importance of the Research Achievements	ミネラルコルチコイド受容体(MR)は腎臓において食塩の再吸収とカリウム排泄のバランスを調節しており、体液のイオン組成や食事の変化に対応して尿細管の働きを柔軟に変化させている。これまでの基礎的・臨床的検討から、Cl/HOC3交換輸送体pendrinの変化がMRの電解質調節作用のスイッチングに関わるキーイベントの一つであることが示されており、食生活習慣と健康の密接な関わり、なかでも食塩による血圧上昇 (食塩感受性高血圧) やカリウム摂取による心血管保護作用の分子基盤が明らかとなってきている。またMRと同様に腎尿細管に高発現するビタミンD受容体の活性化機構について新知見が得られている。