Protective effect of D-alanine against acute kidney injury.

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-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. 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. [ABSTRACT FROM AUTHOR]