Chiral separation has revealed enantio-specific changes in blood and urinary levels of amino acids in kidney diseases. Blood d-/l-serine ratio has been identified to have a correlation with creatinine-based kidney function. However, the mechanism of distinctive behavior in serine enantiomers is not well understood. This study was performed to investigate the role of renal tubules in derangement of serine enantiomers using a mouse model of cisplatin-induced tubular injury. Cisplatin treatment resulted in tubular damage histologically restricted to the proximal tubules and showed a significant increase of serum d-/l-serine ratio with positive correlations to serum creatinine and blood urine nitrogen (BUN). The increased d-/l-serine ratio did not associate with activity of a d-serine degrading enzyme, d-amino acid oxidase, in the kidney. Screening transcriptions of neutral amino acid transporters revealed that Asc-1, found in renal tubules and collecting ducts, was significantly increased after cisplatin-treatment, which correlates with serum d-serine increase. In vitro study using a kidney cell line showed that Asc-1 is induced by cisplatin and mediated influx of d-serine preferably to l-serine. Collectively, these results suggest that cisplatin-induced damage of proximal tubules accompanies Asc-1 induction in tubules and collecting ducts and leads to serum d-serine accumulation.
Mammals exhibit systemic homochirality of amino acids in L -configurations. While ribosomal protein synthesis requires rigorous chiral selection for L -amino acids, both endogenous and microbial enzymes convert diverse L -amino acids to D -configurations in mammals. However, it is not clear how mammals manage such diverse D -enantiomers. Here, we show that mammals sustain systemic stereo dominance of L -amino acids through both enzymatic degradation and excretion of D -amino acids. Multidimensional high performance liquidchromatography analyses revealed that in blood, humans and mice maintain D -amino acids at less than several percent of the corresponding L -enantiomers, while D -amino acids comprise ten to fifty percent of the L -enantiomers in urine and feces. Germ-free experiments showed that vast majority of D -amino acids, except for D -serine, detected in mice are of microbial origin. Experiments involving mice that lack enzymatic activity to catabolize D -amino acids showed that catabolism is central to the elimination of diverse microbial D -amino acids, whereas excretion into urine is of minor importance under physiological conditions. Such active regulation of amino acid homochirality depends on maternal catabolism during the prenatal period, which switches developmentally to juvenile catabolism along with the growth of symbiotic microbes after birth. Thus, microbial symbiosis largely disturbs homochirality of amino acids in mice, whereas active host catabolism of microbial D -amino acids maintains systemic predominance of L -amino acids. Our findings provide fundamental insight into how the chiral balance of amino acids is governed in mammals and further expand the understanding of interdomain molecular homeostasis in host-microbial symbiosis.
Edited by Ned ManteiD-Serine modulates excitatory neurotransmission by binding to N-methyl-D-aspartate glutamate receptors. D-Amino acid oxidase (DAO) degrades D-amino acids, such as D-serine, in the central nervous system, and is associated with neurological and psychiatric disorders. However, cell types that express brain DAO remain controversial, and whether brain DAO influences systemic D-amino acids in addition to brain D-serine remains unclear. Here, we created astrocyte-specific DAO-conditional knockout mice. Knockout in glial fibrillary acidic protein-positive cells eliminated DAO expression in the hindbrain and increased D-serine levels significantly in the cerebellum. Brain DAO did not influence levels of D-amino acids in the forebrain or periphery. These results show that astrocytic DAO regulates D-serine specifically in the hindbrain.
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