CELL-DEATH AND REGENERATION OF RENAL PROXIMAL TUBULAR CELLS IN RATS WITH SUBCHRONIC CADMIUM INTOXICATION

Male Sprague-Dawley rats were injected subcutaneously with 0.6 mg cadm ium (Cd)/kg/day for 8 wk. The subsequent changes in renal proximal tub ules were studied histologically, histochemically, and ultrastructural ly. The urinary and tissue Cd concentrations were determined by atomic absorption spectrophotometry. After 4 wk of exposure, apoptosis was o bserved predominantly in segment S3 along with epithelial regeneration in the affected tubules, and these changes gradually became more pron ounced as the experimental period was prolonged. The apoptotic cells w ere shed into the lumen and were found to contain a large quantity of Cd. Apoptotic cells were counted in paraffin sections after various pe riods of exposure to Cd. Nuclear bromodeoxyuridine uptake, mitotic cou nt, and nuclear density were used as indicators of tubular regeneratio n. 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 apop tosis might be helpful for the efficient excretion of Cd into urine. P rogressive 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 ma rked epithelial regeneration. On the basis of these histological chang es, the critical concentration of Cd required to produce renal tubular damage was estimated to be 600 mu g/g dry tissue.