Kidney is the main target organ of Cd toxicity in humans. Cd-induced nephrotoxicity is thought to be caused by the Cd-
metallothionein complex (
CdMT) that "leaks" out of the liver and is taken up by the kidney. A single injection of
CdMT has therefore been used as a model to study Cd nephropathy for the last 20 years. However, our recent studies reveal discrepancies between renal Cd concentration and nephrotoxic potencies of
CdCl2 and
CdMT. This study was further designed to critically evaluate whether a single injection of
CdMT is an appropriate model to study the mechanism of chronic
CdCl2 nephropathy. Age-matched rats were given multiple sc
injections of either
CdCl2 (0.8 and 1.2 mg Cd/kg) or
CdMT (0.05 mg Cd/kg) daily, 6 days/week for 6 weeks, or a single injection of
CdMT (0.2-0.6 mg Cd/kg i.p. for 24 h), and the nephrotoxicity was compared. Histologically, chronic
CdCl2 or
CdMT administration produced damage to the whole kidney, including tubular cell degeneration, apoptosis, and
atrophy; interstitial
inflammation; glomerular swelling; and
sclerosis. In contrast, acute
CdMT injection produced severe proximal tubule
necrosis as the major feature of its toxicity. Biochemically, chronic exposure to Cd produced
polyuria and calciuria, while
proteinuria, glucosuria, and enzymuria were mild (2-5x). In contrast, acute
CdMT nephrotoxicity was characterized by marked increases in urinary
protein (13x),
glucose (25x),
N-acetyl-beta-d-glucosaminidase (28x),
lactate dehydrogenase (100x), and gamma-glutamyltranspeptidase (160x). Serum levels of
creatinine and blood
urea nitrogen were unchanged following chronic Cd exposure but were markedly elevated (5x) after acute injection of
CdMT. Chronic exposure to either
CdCl2 or
CdMT produced nephrotoxicity at renal Cd concentration of 85 to 110 micrograms/g kidney, while acute
CdMT injection produced nephrotoxicity at only 5 to 7 micrograms/g kidney. In conclusion, the present study indicates that the features and mechanisms of renal injury from chronic Cd exposure are quite different from those produced by a single injection of
CdMT. Therefore, it is proposed that acute
CdMT injection is not an appropriate model for the study of chronic Cd-induced nephrotoxicity.