ツチヤ　ケン   Tsuchiya Ken   土谷　健    所属   医学部 医学科（東京女子医科大学病院）    職種   特任教授
言語種別	英語
発表タイトル	Reduced Flippase Activity in the Early Life of Mature Erythrocytes Is Associated with Their Shortened Lifespan in Renal Anemia
会議名	Kidney Week 2024
主催者	American Society of Nephrology
学会区分	国際学会及び海外の学会
発表形式	ポスター掲示
講演区分	一般
発表者・共同発表者	◎Seki Momoko, Arashiki Nobuto, Manabe Shun, Kataoka Hiroshi, Tsuchiya Ken, Hoshino Junichi, Nakamura Fumio,
発表年月日	2024/10/24
国名	アメリカ合衆国
開催地 （都市, 国名）	San Diego, USA
開催期間	2024/10/24～2024/10/27
概要	Background The lifespan of mature erythrocytes in renal anemia patients is shortened (approximately 70 days) compared to that of healthy individuals (120 days), but its pathogenesis is unclear. Previously, we reported that in healthy senescent erythrocytes decreased intracellular K+ and ATP levels, and flippase molecule ATP11C, lead to decreased flippase activity, resulting in increased phosphatidylserine (PS) exposure, a removal sign for macrophages (Seki M, 2020). Our recent investigations have revealed that senescent erythrocytes from renal anemia patients also exhibited decreased flippase activity, leading to PS exposure, mainly due to K+ loss. This study demonstrated that senescent erythrocytes in patients were younger than the senescent erythrocytes in healthy individuals. We additionally conducted a quantitative proteome analysis of the membrane proteins obtained from young and senescent erythrocytes of patients to identify candidates involved in K+ loss. Methods Erythrocytes from patients undergoing maintenance hemodialysis and from healthy volunteers were fractionated into young (light) and senescent (heavy) populations using a Percoll-density gradient according to our previous report. HbA1c was measured in fractionated erythrocytes as a marker of their age. We conducted a quantitative MS/MS using the Tandem Mass Tagging labeling system on membrane proteins from young and senescent erythrocytes of renal anemia patients (n=3). Results Although the number of senescent erythrocytes in patients bore a similarity to that of healthy humans, HbA1c levels in the heavy fractions of patients were lower than levels in healthy individuals. The proteomic analysis of patients’ membranes presented oxidation-modified Transient Receptor Potential Melastatin 2 (TRPM2), an oxidation-sensitive calcium channel, and a sufficient amount of Piezo1, a mechanosensitive calcium channel. Both are potent contributors to activate calcium-dependent K+ leakage (Gardos effect). Conclusion In the early life of mature erythrocytes in renal anemia patients, reduced flippase activity causes PS exposure due to K+ loss. We identified two responsible candidates for K+ leakage, TRPM2 and Piezo1, which could serve as novel therapeutic targets for renal anemia.