| Project/Area Number |
16K15465
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Kidney internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Reiko Inagi 東京大学, 医学部附属病院, 特任准教授 (50232509)
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| 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)
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| Research Collaborator |
ISHIMOTO Yu
OKADA Akira
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| Project Period (FY) |
2016-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| 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 / 近位尿細管上皮細胞 / 尿細管間質障害 / 腎臓老化 / 腎臓病態生理 / 小胞体ストレス / 蛋白質恒常性 |
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| 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.
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