Nephrotoxicity of D-propargylglycine in mice

When D-propargylglycine was injected intraperitoneally into mice, polyuria, glycosuria, and aminoaciduria were observed as has been previously reporte d in rats. The urine of the mice treated with D-propargylglycine contained twice as much protein as that of the control mice. Polyacrylamide gel elect rophoresis showed a new protein of approximately 62 kDa in the urine of the D-propargylglycine-treated mice. Protein sequencing revealed that this pro tein was serum albumin. Since the above-mentioned symptoms suggested dysfun ction of the renal proximal tubules, the activity of urinary N-acetyl-beta -D-glucosaminidase, a marker enzyme of injury to the proximal tubules, was measured. The urinary enzyme activity was 2.6 times higher in the D-proparg ylglycine-treated mice than in the control mice. Light- and electron-micros copy showed degenerative and necrotic cells in the straight part of the pro ximal tubules of the treated mice. However, none of these symptoms was obse rved in D-propargylglycine-treated mutant mice, lacking D-amino-acid oxidas e. These results indicate that D-progargylglycine itself is not nephrotoxic but its metabolite produced by the D-aminoacid oxidase reaction is nephrot oxic and injures proximal tubular cells, resulting in an impairment of the reabsorption of water, glucose, amino acids, and proteins.