TY - JOUR
T1 - Gut microbiota-derived D-serine protects against acute kidney injury
AU - Nakade, Yusuke
AU - Iwata, Yasunori
AU - Furuichi, Kengo
AU - Mita, Masashi
AU - Hamase, Kenji
AU - Konno, Ryuichi
AU - Miyake, Taito
AU - Sakai, Norihiko
AU - Kitajima, Shinji
AU - Toyama, Tadashi
AU - Shinozaki, Yasuyuki
AU - Sagara, Akihiro
AU - Miyagawa, Taro
AU - Hara, Akinori
AU - Shimizu, Miho
AU - Kamikawa, Yasutaka
AU - Sato, Kouichi
AU - Oshima, Megumi
AU - Yoneda-Nakagawa, Shiori
AU - Yamamura, Yuta
AU - Kaneko, Shuichi
AU - Miyamoto, Tetsuya
AU - Katane, Masumi
AU - Homma, Hiroshi
AU - Morita, Hidetoshi
AU - Suda, Wataru
AU - Hattori, Masahira
AU - Wada, Takashi
PY - 2018/10/18
Y1 - 2018/10/18
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.97957
DO - 10.1172/jci.insight.97957
M3 - Article
C2 - 30333299
AN - SCOPUS:85063243335
SN - 2379-3708
VL - 3
JO - JCI insight
JF - JCI insight
IS - 20
ER -