Nephrotoxicity of D-proparglyglycine in mice.
When D-propargylglycine was injected intraperitoneally into mice, polyuria, glycosuria, and aminoaciduria were observed as has been previously reported in rats. The urine of the mice treated with D-propargylglycine contained twice as much protein as that of the control mice. Polyacrylamide gel electrophoresis showed a new protein of approximately 62 kDa in the urine of the D-propargylglycine-treated mice. Protein sequencing revealed that this protein was serum albumin. Since the above-mentioned symptoms suggested dysfunction 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-propargylglycine-treated mice than in the control mice. Light- and electron-microscopy showed degenerative and necrotic cells in the straight part of the proximal tubules of the treated mice. However, none of these symptoms was observed in D-propargylglycine-treated mutant mice, lacking D-amino-acid oxidase. These results indicate that D-propargylglycine itself is not nephrotoxic but its metabolite produced by the D-amino-acid oxidase reaction is nephrotoxic and injures proximal tubular cells, resulting in an impairment of the reabsorption of water, glucose, amino acids, and proteins.
Konno
R
R
Department of Microbiology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. konno@dokkyomed.ac.jp
Ikeda
M
M
Yamaguchi
K
K
Ueda
Y
Y
Niwa
A
A
D000480:Alkynes / Q000378:metabolism / Q000633:toxicity*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D007668:Kidney / Q000187:drug effects*; D051379:Mice; D008969:Molecular Sequence Data; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000480:Alkynes; D000596:Amino Acids; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; C009055:propargylglycine; D003605:D-Amino-Acid Oxidase; D005998:Glycine