Cadmium nephrotoxicity and evacuation from the body in a rat modeled subchronic intoxication

Abstract

Background : Cadmium (Cd) is an important industrial pollutant, although its mechanism of toxicity has not been completely clarified. We studied Cd-induced subchronic nephrotoxicity and the cadmium evacuation system in rats and cultured human renal tubular cells. Methods : Male Sprague-Dawley rats were subcutaneously injected with 0.6 mg Cd/kg per day for periods of 3, 5 and 8 weeks. The concentration of Cd in urine, serum and kidneys was measured by atomic absorption spectrophotometry. Nephrotoxicity was evaluated based on the urinary concentration of b 2 microglobulin (B2MG) and histopathological findings. Apoptotic cells were detected by nick-end labeling and DNA laddering, and were based on the level of caspase-3 activity. Cadmium-induced toxicity was also studied in cultured human renal tubular cells.Results : Nephrotoxicity was detected after 4 weeks of exposure to Cd, because Cd and B2MG appeared in urine. The tissue concentration of Cd increased linearly throughout the 8 weeks of exposure to Cd. The concentration of renal Cd did not change in the 3-week exposure group, but it decreased after withdrawal of Cd in the 5-week exposure group, suggesting an active Cd excretion mechanism started after the 4th week. The threshold Cd concentration for nephrotoxicity was 150 micrograms/gram wet tissue, at which concentration histological tubular damage started. Although the kidneys presented mainly necrosis, apoptosis was observed at weeks 4 and 5, before renal tubular necrosis occurred . In vitro DNA laddering was observed and peak caspase-3 activity was detected when the cells were exposed to the threshold concentration of Cd. Conclusion : Cadmium was effectively evacuated from the body by exfoliation of damaged renal tubular cells presenting focal tubular necrosis after the renal Cd concentration reached the threshold. Apoptosis may be involved in the regulation of Cd-induced nephrotoxicity.

Health effects of cadmium exposure in the general environment in Japan with special reference to the lower limit of the benchmark dose as the threshold level of urinary cadmium

“…In studies of health effects caused by exposure to cadmium, the urinary cadmium concentration is often used as an indicator of internal dose. Reports on cadmium levels of workers and animals have shown a close relationship between urinary cadmium excretion and the total body burden of cadmium (23)(24)(25)(26)(27). We found that urinary cadmium increased with the increasing lifetime cadmium intake among inhabitants of the general environment (10).…”

Influence of N-acetylcysteine on renal toxicity of cadmium in rats

“…Additionally, discontinuing the toxic agent (Cd) in this group could have decreased FENa. In this study, it was demonstrated that NAC decreases Na loss in the kidney, and this is another sign of the preventive effect of NAC on Cd-induced nephrotoxicity Cd accumulation in rat kidney results in serious histopathological changes, including tubular vacuolation, degeneration, necrosis, interstitial nephritis, and fibrosis [3,[32][33][34]. On the other hand, NAC has vasodilator effects to enhance tissue perfusion [35].…”

Protective Effect of Quercetin Against Renal Toxicity Induced by Cadmium in Rats

“…High levels of Cd are clearly capable of causing proximal tubule necrosis (22,24). However, other studies indicate that the early stages of Cd nephrotoxicity primarily involve apoptosis of proximal tubule epithelial cells, with little evidence of necrosis (25,26). Moreover, results of several recent studies suggest that the early stages of Cd-nephrotoxicity may involve changes in cell adhesion molecule function and cytoskeletal organization that occur before the onset of either necrotic or apoptotic death of proximal tubule epithelial cells (27,28).…”

“…In a more recent study, Aoyagi et al (25) noted an increase in the number of TUNEL-labeled cells in the renal cortex of Cd treated rats after 4 and 5 weeks of exposure, but the level of apoptotic labeling was much less pronounced after 6 and 8 weeks of exposure. However, no quantitative data was included in their analysis.…”