Iwata Yasunori, Nakade Yusuke, Kitajima Shinji, Yoneda-Nakagawa Shiori, Oshima Megumi, Sakai Norihiko, Ogura Hisayuki, Sato Koichi, Toyama Tadashi, Yamamura Yuta, Miyagawa Taro, Yamazaki Hiroka, Hara Akinori, Shimizu Miho, Furuichi Kengo, Mita Masashi, Hamase Kenji, Tanaka Tomohiro, Nishida Motohiro, Muramatsu Wataru, Yamamoto Hisashi, Shichino Shigeyuki, Ueha Satoshi, Matsushima Kouji, Wada Takashi
Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan.
Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.
Am J Physiol Renal Physiol. 2022 Jun 1;322(6):F667-F679. doi: 10.1152/ajprenal.00198.2021. Epub 2022 Apr 18.
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 -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 genes encoding NMDA receptor subtypes were expressed in TECs. Hypoxic conditions change the gene expression of , , and 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 and , 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. 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.
近期研究揭示了氨基酸手性与疾病之间的联系。我们之前报道过，在小鼠急性肾损伤（AKI）模型中，肠道微生物群会产生多种D-氨基酸。在此，我们进一步探究了D-丙氨酸（D-Ala）在AKI中的病理生理作用。在小鼠AKI模型中评估了D-Ala的水平。我们分析了肾小管上皮细胞（TECs）中D-Ala的受体——N-甲基-D-天冬氨酸（NMDA）受体的转录本。随后在体内和体外评估了D-Ala的治疗效果。最后，评估了AKI患者血浆中D-Ala的水平。编码NMDA受体亚型的基因在TECs中表达。缺氧条件会改变这些基因的表达，而D-Ala可保护TECs免受缺氧相关的细胞损伤，并在缺氧后诱导其增殖。这些保护作用与D-Ala的手性有关。D-Ala通过NMDA受体信号传导抑制活性氧（ROS）的产生并改善线粒体膜电位。在缺血再灌注（I/R）诱导后，粪便、血浆和尿液中D-Ala与L-Ala的比例增加。此外，肠杆菌科细菌，如大肠杆菌和肺炎克雷伯菌，会产生D-Ala。口服D-Ala可改善小鼠I/R诱导后的肾损伤。肾小管细胞中NMDA亚基NR1的缺乏会加重AKI中的肾损伤。此外，AKI患者血浆中D-Ala的水平升高，并反映了肾功能水平。总之，D-Ala对I/R诱导的肾损伤具有保护作用。此外，D-Ala的血浆水平反映了AKI患者的估计肾小球滤过率。D-Ala可能是AKI一个有前景的治疗靶点和潜在生物标志物。D-丙氨酸对I/R诱导的肾损伤具有保护作用。D-Ala抑制ROS的产生并改善线粒体膜电位，从而减少缺氧刺激引起的TEC坏死。给予D-Ala可保护小鼠肾小管免受I/R损伤。此外，AKI患者血浆中D-Ala的水平与估算肾小球滤过率呈负相关。我们的数据表明，D-Ala是一个有吸引力的治疗靶点和AKI的潜在生物标志物。
