TY - JOUR
T1 - Protective effect of D-alanine against acute kidney injury
AU - Iwata, Yasunori
AU - Nakade, Yusuke
AU - Kitajima, Shinji
AU - Yoneda-Nakagawa, Shiori
AU - Oshima, Megumi
AU - Sakai, Norihiko
AU - Ogura, Hisayuki
AU - Sato, Koichi
AU - Toyama, Tadashi
AU - Yamamura, Yuta
AU - Miyagawa, Taro
AU - Yamazaki, Hiroka
AU - Hara, Akinori
AU - Shimizu, Miho
AU - Furuichi, Kengo
AU - Mita, Masashi
AU - Hamase, Kenji
AU - Tanaka, Tomohiro
AU - Nishida, Motohiro
AU - Muramatsu, Wataru
AU - Yamamoto, Hisashi
AU - Shichino, Shigeyuki
AU - Ueha, Satoshi
AU - Matsushima, Kouji
AU - Wada, Takashi
N1 - Funding Information:
This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research on Innovative Areas program (Inflammation Cellular Sociology, 17H06394, to Y.I., N.S., K.F., S.S., S.U., K.M., and T.W.), JSPS KAKENHI (18K08426, to Y.I.), Kanazawa University SAKIGAKE project 2020 (to Y.I.), and Joint Research of the Exploratory Research Center on Life and Living Systems (ExCELLS Program No. 20–310).
Publisher Copyright:
© 2022 the American Physiological Society.
PY - 2022
Y1 - 2022
N2 - Recent studies have revealed the connection between amino acid chirality and diseases. We have previously reported that the gut microbiota produces various D-amino acids in a murine acute kidney injury (AKI) model. Here, we further explored the pathophysiological role of D-alanine (D-Ala) in AKI. Levels of D-Ala were evaluated in a murine AKI model. We analyzed transcripts of the N-methyl-Daspartate (NMDA) receptor, a receptor for D-Ala, in tubular epithelial cells (TECs). The therapeutic effect of D-Ala was then assessed in vivo and in vitro. Finally, the plasma level of D-Ala was evaluated in patients with AKI. The Grin genes encoding NMDA receptor subtypes were expressed in TECs. Hypoxic conditions change the gene expression of Grin1, Grin2A, and Grin2B. D-Ala protected TECs from hypoxia-related cell injury and induced proliferation after hypoxia. These protective effects are associated with the chirality of D-Ala. D-Ala inhibits reactive oxygen species (ROS) production and improves mitochondrial membrane potential, through NMDA receptor signaling. The ratio of D-Ala to L-Ala was increased in feces, plasma, and urine after the induction of ischemia-reperfusion (I/R). Moreover, Enterobacteriaceae, such as Escherichia coli and Klebsiella oxytoca, produce D-Ala. Oral administration of D-Ala ameliorated kidney injury after the induction of I/R in mice. Deficiency of NMDA subunit NR1 in tubular cells worsened kidney damage in AKI. In addition, the plasma level of D-Ala was increased and reflected the level of renal function in patients with AKI. In conclusion, D-Ala has protective effects on I/R-induced kidney injury. Moreover, the plasma level of D-Ala reflects the estimated glomerular filtration rate in patients with AKI. D-Ala could be a promising therapeutic target and potential biomarker for AKI.
AB - Recent studies have revealed the connection between amino acid chirality and diseases. We have previously reported that the gut microbiota produces various D-amino acids in a murine acute kidney injury (AKI) model. Here, we further explored the pathophysiological role of D-alanine (D-Ala) in AKI. Levels of D-Ala were evaluated in a murine AKI model. We analyzed transcripts of the N-methyl-Daspartate (NMDA) receptor, a receptor for D-Ala, in tubular epithelial cells (TECs). The therapeutic effect of D-Ala was then assessed in vivo and in vitro. Finally, the plasma level of D-Ala was evaluated in patients with AKI. The Grin genes encoding NMDA receptor subtypes were expressed in TECs. Hypoxic conditions change the gene expression of Grin1, Grin2A, and Grin2B. D-Ala protected TECs from hypoxia-related cell injury and induced proliferation after hypoxia. These protective effects are associated with the chirality of D-Ala. D-Ala inhibits reactive oxygen species (ROS) production and improves mitochondrial membrane potential, through NMDA receptor signaling. The ratio of D-Ala to L-Ala was increased in feces, plasma, and urine after the induction of ischemia-reperfusion (I/R). Moreover, Enterobacteriaceae, such as Escherichia coli and Klebsiella oxytoca, produce D-Ala. Oral administration of D-Ala ameliorated kidney injury after the induction of I/R in mice. Deficiency of NMDA subunit NR1 in tubular cells worsened kidney damage in AKI. In addition, the plasma level of D-Ala was increased and reflected the level of renal function in patients with AKI. In conclusion, D-Ala has protective effects on I/R-induced kidney injury. Moreover, the plasma level of D-Ala reflects the estimated glomerular filtration rate in patients with AKI. D-Ala could be a promising therapeutic target and potential biomarker for AKI.
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U2 - 10.1152/ajprenal.00198.2021
DO - 10.1152/ajprenal.00198.2021
M3 - Article
C2 - 35435002
AN - SCOPUS:85130632268
SN - 1931-857X
VL - 322
SP - F667-F679
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
IS - 6
ER -