Acute nephrotoxicity of a carcinogenic iron chelate. Selective inhibition of a proteolytic conversion of alpha 2U-globulin to the kidney fatty acid-binding protein.
The mechanism of acute nephrotoxicity of an iron chelate in vivo has been investigated. Administration of a renal carcinogen ferric nitrilotriacetate (Fe-NTA) (15 mg Fe/kg body weight, intraperitoneally) led to selective loss of a renal protein with an apparent molecular mass of 17 kDa. Analysis of the 17 kDa protein by NH2-terminal sequence demonstrated its identity over 16 NH2-terminal residues as a kidney fatty acid-binding protein (k-FABP) that is a proteolytically modified form of alpha 2U-globulin, a major urinary protein of adult male rats. An immunochemical study using anti-alpha 2U-globulin polyclonal antibodies confirmed that a single injection of Fe-NTA led to a decrease in k-FABP levels. However, a 19-kDa protein identical to the alpha 2U-globulin progressively appeared in the kidney, suggesting that the proteolytic processing of alpha 2U-globulin in the renal proximal tubules was suppressed by the treatment with Fe-NTA. By monitoring k-FABP and its precursor alpha 2U-globulin, it was determined that repeated exposure to Fe-NTA caused suppression of both proteolytic and endocytotic activity of the kidney. The implications of these data in relation to the nephrotoxicity of Fe-NTA are discussed.
Uchida
K
K
Laboratory of Food and Biodynamics, Nagoya University School of Agriculture, Japan.
Fukuda
A
A
Kawakishi
S
S
Toyokuni
S
S
Hiai
H
H
Ikeda
S
S
Horio
F
F
D000510:Alpha-Globulins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002352:Carrier Proteins / Q000378:metabolism*; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism; D005290:Ferric Compounds / Q000633:toxicity*; D007502:Iron Chelating Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
D000510:Alpha-Globulins; D002273:Carcinogens; D002352:Carrier Proteins; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D005290:Ferric Compounds; D007502:Iron Chelating Agents; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C013803:alpha 2u globulin; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate