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Protective effect of d-alanine against acute kidney injury.

Authors :
Iwata Y
Nakade Y
Kitajima S
Yoneda-Nakagawa S
Oshima M
Sakai N
Ogura H
Sato K
Toyama T
Yamamura Y
Miyagawa T
Yamazaki H
Hara A
Shimizu M
Furuichi K
Mita M
Hamase K
Tanaka T
Nishida M
Muramatsu W
Yamamoto H
Shichino S
Ueha S
Matsushima K
Wada T
Source :
American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2022 Jun 01; Vol. 322 (6), pp. F667-F679. Date of Electronic Publication: 2022 Apr 18.
Publication Year :
2022

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-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. NEW & NOTEWORTHY d-Alanine has protective effects on I/R-induced kidney injury. d-Ala inhibits ROS production and improves mitochondrial membrane potential, resulting in reduced TEC necrosis by hypoxic stimulation. The administration of d-Ala protects the tubules from I/R injury in mice. Moreover, the plasma level of d-Ala is conversely associated with eGFR in patients with AKI. Our data suggest that d-Ala is an appealing therapeutic target and a potential biomarker for AKI.

Details

Language :
English
ISSN :
1522-1466
Volume :
322
Issue :
6
Database :
MEDLINE
Journal :
American journal of physiology. Renal physiology
Publication Type :
Academic Journal
Accession number :
35435002
Full Text :
https://doi.org/10.1152/ajprenal.00198.2021