A morphological and biochemical study of the effects of L-cysteine on the renal uptake and nephrotoxicity of cadmium

Abstract

In JCLR and Wistar-Porton rats renal concentrations of Cd2+ were maximal (21-22 micrograms Cd2+/g wet wt tissue) at 1 and 4 h respectively after the administration of CdCl2 (10 micromol, 1-12 mg Cd2+/kg body wt) together with L-cysteine (5 mmol/kg body wt). Synthesis of metallothionein in the kidney in response to the uptake of Cd2+, which occurred between 2 and 7 h after treatment in the Wistar-Porton rat, affected the distribution of Cd2+ between proteins of the renal soluble fraction, but not between the particulate components and, at both times, about 40% of the total Cd2+ was associated with the heterogeneous nuclei + cell debris fraction. Autoradiographic studies with 109CdCl2 revealed that Cd2+, accumulated by the kidney under these conditions, was not uniformly distributed throughout the renal cortex, but was concentrated unevenly in proximal tubules in the outer stripe of the outer zone of the medulla. Pathological changes, which were correlated with the concentrations of accumulated Cd2+ and were limited to the S3 segments of the proximal tubules, were apparent by light microscopy at 4 h after the administration of Cd2+ + cysteine and progressed with time. Thus by 7 h the lesion had extended to include almost the whole of the outer stripe of the outer zone of the medulla and, by 24 h the cells of the affected epithelia showed extensive necrosis and karyorrhexis. At this, as at earlier times, the cortex appeared to be undamaged. Neither these nor other morphological changes were observed in the kidneys of animals that had been dosed with either Cd2+, or L-cysteine alone. Within 60 min of the administration of Cd2+ + cysteine an increase in the number of endocytotic vesicles in the apical cytoplasm of the proximal tubular epithelium was observed by electron microscopy. Subsequent cytoplasmic vesiculation, which was conspicuous at 2 h, was extensive and widespread in both the apical and basal regions of the cytoplasm at 4 h. In some cells at this time the nuclei were irregular in shape; the mitochondria were swollen and their cristae were disorganized. As, after the administration of either Cd2+ or cadmium-metallothionein, damage is known to occur in the S1 and S2 segments of proximal tubules throughout the cortex, the Cd2+ + cysteine combination does not provide an exact model which reproduces in a short time the effects of long-term, low level exposure to Cd2+. Nevertheless it is suggested that the toxic mechanisms are the same after either treatment with Cd2+ + cysteine or continual exposure to Cd2+, but are limited to different segments of the proximal tubules. Possible mechanisms of toxicity are discussed.