Male Sprague-Dawley rats were injected subcutaneously with 0.6 mg cadmium (Cd)/kg/day for 8 wk. The subsequent changes in renal proximal tubules were studied histologically, histochemically, and ultrastructurally. The urinary and tissue Cd concentrations were determined by atomic absorption spectrophotometry. After 4 wk of exposure, apoptosis was observed predominantly in segment S3 along with epithelial regeneration in the affected tubules, and these changes gradually became more pronounced as the experimental period was prolonged. The apoptotic cells were shed into the lumen and were found to contain a large quantity of Cd. Apoptotic cells were counted in paraffin sections after various periods of exposure to Cd. Nuclear bromodeoxyuridine uptake, mitotic count, and nuclear density were used as indicators of tubular regeneration. A correlation was found between the numerical increase of apoptotic cells and the rate of urinary Cd excretion, and the rate of increase in the tissue Cd concentration had a tendency to reduce after 4 wk as the rate of urinary Cd increased. These observations suggest that apoptosis might be helpful for the efficient excretion of Cd into urine. Progressive increases in the preceding indicators of regeneration were observed. From our results, it appears that Cd-induced tubular damage, i.e., cell deletion due to apoptosis, is reversible as a result of marked epithelial regeneration. On the basis of these histological changes, the critical concentration of Cd required to produce renal tubular damage was estimated to be 600 μg/g dry tissue.
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