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.