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Kidney Week

Abstract: TH-PO094

Gut Microbiota Derived D-Alanine Ameliorates Kidney Damage via Protection of Mitochondria in Murine AKI

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Iwata, Yasunori, Kanazawa Daigaku, Kanazawa, Ishikawa, Japan
  • Nakade, Yusuke, Kanazawa Daigaku, Kanazawa, Ishikawa, Japan
  • Wada, Takashi, Kanazawa Daigaku, Kanazawa, Ishikawa, Japan
Background

We have previously reported that the gut microbiota produces various D-amino acids including D-Serine (Ser) and D-Alanine (Ala) in a murine acute kidney injury (AKI) model. D-Ser showed the renoprotective effect on ischemia-reperfusion (I/R) induced kidney injury. Here, we further explored the pathophysiological role of D-Ala in AKI.

Methods

We analyzed transcripts of the N-methyl-d-aspartate (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.

Results

The Grin genes encoding NMDA receptor subtypes were expressed in TECs. D-Ala protected TECs from hypoxia-related cell injury and induced proliferation after hypoxia. 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 I/R. Moreover, Enterobacteriaceae 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.

Conclusion

D-Ala ameliorates I/R-induced kidney injury via protection of mitochondria. 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.