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Gut microbiota–derived D-serine protects against acute kidney injury
Yusuke Nakade, … , Masahira Hattori, Takashi Wada
Yusuke Nakade, … , Masahira Hattori, Takashi Wada
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e97957. https://doi.org/10.1172/jci.insight.97957.
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Research Article Microbiology Nephrology

Gut microbiota–derived D-serine protects against acute kidney injury

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Abstract

Gut microbiota–derived metabolites play important roles in health and disease. D–amino acids and their L-forms are metabolites of gut microbiota with distinct functions. In this study, we show the pathophysiologic role of D–amino acids in association with gut microbiota in humans and mice with acute kidney injury (AKI). In a mouse kidney ischemia/reperfusion model, the gut microbiota protected against tubular injury. AKI-induced gut dysbiosis contributed to the altered metabolism of D–amino acids. Among the D–amino acids, only D-serine was detectable in the kidney. In injured kidneys, the activity of D–amino acid oxidase was decreased. Conversely, the activity of serine racemase was increased. The oral administration of D-serine mitigated the kidney injury in B6 mice and D-serine–depleted mice. D-serine suppressed hypoxia-induced tubular damage and promoted posthypoxic tubular cell proliferation. Finally, the D-serine levels in circulation were significantly correlated with the decrease in kidney function in AKI patients. These results demonstrate the renoprotective effects of gut-derived D-serine in AKI, shed light on the interactions between the gut microbiota and the kidney in both health and AKI, and highlight D-serine as a potential new therapeutic target and biomarker for AKI.

Authors

Yusuke Nakade, Yasunori Iwata, Kengo Furuichi, Masashi Mita, Kenji Hamase, Ryuichi Konno, Taito Miyake, Norihiko Sakai, Shinji Kitajima, Tadashi Toyama, Yasuyuki Shinozaki, Akihiro Sagara, Taro Miyagawa, Akinori Hara, Miho Shimizu, Yasutaka Kamikawa, Kouichi Sato, Megumi Oshima, Shiori Yoneda-Nakagawa, Yuta Yamamura, Shuichi Kaneko, Tetsuya Miyamoto, Masumi Katane, Hiroshi Homma, Hidetoshi Morita, Wataru Suda, Masahira Hattori, Takashi Wada

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Figure 3

Dysbiosis induced by AKI alters the balance of D/L–amino acids.

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Dysbiosis induced by AKI alters the balance of D/L–amino acids.
(A and B...
(A and B) Although some free D–amino acids were detected in the feces of B6 mice with or without I/R, only D-serine can be detected in the kidney. (C) Free D-serine is increased in the feces, plasma, kidney, and urine after the I/R. (D) No free D–amino acids, except D-asparagine and D-aspartic acid, are detected in the feces of Gf B6 mice before and after I/R. (E) DAO activity is decreased in the kidney after the I/R injury. (F) SRR activity is increased in the injured kidney. Data are shown as mean ± SEM. Statistical analysis was performed using Student’s t test (C, E, and F). *P < 0.05, **P < 0.01. UD, undetectable.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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