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.