Pathophysiological role of D-amino acid on proteostasis in the kidney
| 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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Report
(3 results)
Research Products
(94 results)
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[Journal Article] Palmitate deranges erythropoietin production via ATF4 activation of unfolded protein response2018
Author(s)
Thitinun Anusornvongchai, Masaomi Nangaku, Tzu-Ming Jao, Chia-Hsien Wu, Yu Ishimoto, Hiroshi Maekawa, Tetsuhiro Tanaka, Akira Shimizu, Masayuki Yamamoto, Norio Suzuki, Ryoji Sassa, and Reiko Inagi
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Journal Title
Related Report
Peer Reviewed / Open Access
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[Journal Article] Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease2017
Author(s)
Ishimoto Y, Inagi R, Yoshihara D, Kugita M, Nagao S, Shimizu A, Takeda N, Wake M, Honda K, Zhou J, Nangaku M
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Journal Title
Mol Cell Biol
Volume: e-Pub
Issue: 24
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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