Ischemic Acute Kidney Injury Perturbs Homeostasis of Serine Enantiomers in the Body Fluid in Mice: Early Detection of Renal Dysfunction Using the Ratio of Serine Enantiomers

Abstract

The imbalance of blood and urine amino acids in renal failure has been studied mostly without chiral separation. Although a few reports have shown the presence of D-serine, an enantiomer of L-serine, in the serum of patients with severe renal failure, it has remained uncertain how serine enantiomers are deranged in the development of renal failure. In the present study, we have monitored serine enantiomers using a two-dimensional HPLC system in the serum and urine of mice after renal ischemia-reperfusion injury (IRI), known as a mouse model of acute kidney injury. In the serum, the level of D-serine gradually increased after renal IRI in parallel with that of creatinine, whereas the L-serine level decreased sharply in the early phase after IRI. The increase of D-serine was suppressed in part by genetic inactivation of a D-serine-degrading enzyme, D-amino acid oxidase (DAO), but not by disruption of its synthetic enzyme, serine racemase, in mice. Renal DAO activity was detected exclusively in proximal tubules, and IRI reduced the number of DAO-positive tubules. On the other hand, in the urine, D-serine was excreted at a rate nearly triple that of L-serine in mice with sham operations, indicating that little D-serine was reabsorbed while most L-serine was reabsorbed in physiological conditions. IRI significantly reduced the ratio of urinary D−/L-serine from 2.82±0.18 to 1.10±0.26 in the early phase and kept the ratio lower than 0.5 thereafter. The urinary D−/L-serine ratio can detect renal ischemia earlier than kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL) in the urine, and more sensitively than creatinine, cystatin C, or the ratio of D−/L-serine in the serum. Our findings provide a novel understanding of the imbalance of amino acids in renal failure and offer a potential new biomarker for an early detection of acute kidney injury.

Monitoring of the influence of long‐term oxidative stress and ischemia on the condition of kidneys using solid‐phase microextraction chemical biopsy coupled with liquid chromatography–high‐resolution mass spectrometry

“…D‐amino acids have been recently discovered as naturally occurring in human stereoisomers of well‐known l ‐amino acids, and are now considered to serve as potential biomarkers, especially in renal pathophysiology. Several chiral metabolomics studies have reported on the impact of d ‐serine on kidney dysfunction [47–49]. Hesaka et al.…”

Enantiomeric Ratio of Amino Acids as a Tool for Determination of Aging and Disease Diagnostics by Chromatographic Measurement

“…D-isomers of all investigated AAs were found in rat urine but at various enantiomeric ratios. The developed procedure was also successfully used for the determination of D-and L-Ser in urine and serum of mice after renal ischemia-reperfusion injury (IRI), known as a mouse model of acute kidney injury [64]. The level of D-Ser gradually increased in serum after renal IRI in parallel with creatinine, whereas the L-Ser level decreased sharply in the early phase after IRI.…”

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐13C]alanine

“…Although it is also expressed in hepatocytes, in the central nervous system (CNS) and in polymorphonuclear (PMN) leukocytes, the physiological and pathological role of d ‐amino acids and DAO in these tissues is not completely understood. DAO has been shown to play a detoxifying role in the kidneys, as it helps maintain low d ‐amino acid levels . Since it controls d ‐serine levels, DAO activity in the CNS has been associated with conditions affecting N ‐methyl‐ d ‐aspartate (NMDA) receptor signaling/dysfunction, including schizophrenia, amyotrophic lateral sclerosis and Alzheimer's disease .…”