Serum d-serine accumulation after proximal renal tubular damage involves neutral amino acid transporter Asc-1

Abstract

Abstract 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.