Protective effect of D-alanine against acute kidney injury

Yasunori Iwata, Yusuke Nakade, Shinji Kitajima, Shiori Yoneda-Nakagawa, Megumi Oshima, Norihiko Sakai, Hisayuki Ogura, Koichi Sato, Tadashi Toyama, Yuta Yamamura, Taro Miyagawa, Hiroka Yamazaki, Akinori Hara, Miho Shimizu, Kengo Furuichi, Masashi Mita, Kenji Hamase, Tomohiro Tanaka, Motohiro Nishida, Wataru MuramatsuHisashi Yamamoto, Shigeyuki Shichino, Satoshi Ueha, Kouji Matsushima, Takashi Wada

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)F667-F679
JournalAmerican Journal of Physiology - Renal Physiology
Volume322
Issue number6
DOIs
Publication statusPublished - 2022

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

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