Pathophysiological role of D-amino acid on proteostasis in the kidney

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K15465
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Reiko Inagi 東京大学, 医学部附属病院, 特任准教授 (50232509)
• Co-Investigator(Kenkyū-buntansha): 川上 貴久 東京大学, 医学部附属病院, 助教 (10722093) ; 南学 正臣 東京大学, 医学部附属病院, 教授 (90311620) ; 田中 哲洋 東京大学, 医学部附属病院, 講師 (90508079) ; 加藤 秀樹 東京大学, 医学部附属病院, 講師 (90625237) ; 吉田 瑶子 東京大学, 医学部附属病院, 特任研究員 (90649443)
• Research Collaborator: ISHIMOTO Yu ; OKADA Akira
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: D-アミノ酸 / D-セリン / 尿細管上皮細胞 / 尿細管老化 / SASP / アポトーシス / 細胞周期停止 / 慢性腎臓病

Outline of Final Research Achievements

We found that D-serine markedly induced cellular senescence and apoptosis in a human proximal tubular cell line, HK-2, and primary culture of human renal tubular cells. The former was accompanied by G2/M cell cycle arrest and senescence-associated secretory phenotype (SASP), including pro-fibrotic and pro-inflammatory factors, contributing to tubulointerstitial fibrosis. Integrated stress response mediated by GCN2 (GCN2-ATF4-CHOP pathway) played a central role in D-serine-induced cell toxicity and pro-fibrotic phenotypes, accelerating CKD progression and kidney aging. D-serine upregulated the L-serine synthesis pathway and L-serine administration ameliorated D-serine-induced tubular cell arrest, indicating that D-/L-serine ratio is important in tubular homeostasis.
In conclusion, this study unveils molecular mechanisms underlying D-serine-induced tubular damage and pro-fibrotic phenotypes, suggesting that D-serine is a uremic toxin involved in CKD pathogenesis.

Free Research Field

分子腎臓学