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Cadmium-induced Mitochondrial Damage and Intervention

Author: PanXiaoHai
Tutor: JinTai
School: Fudan University
Course: Health Toxicology
Keywords: Cadmium Liver Kidney Mitochondria Respiratory function Swelling Membrane potential Mitochondrial activity Superoxide radicals
CLC: R114
Type: Master's thesis
Year: 2010
Downloads: 155
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Abstract

Cadmium is an industrial and environmental pollutants the human intake easy savings in the body causing the body's multi-system, multi-organ damage. Liver, kidney cadmium accumulate in the body and damage the main target organs. Inside the cell, the mitochondria because for the oxidation can become an important role in the mediated apoptosis control the key subcellular organelles of the cell life and death. At the same time, the mitochondria is sensitive to external stimuli and damage subcellular organelles. In this study, observe the ultrastructure of the renal cortex, and the separation preparation of rat liver, kidney mitochondrial respiratory function, swelling effect, the membrane potential, mitochondrial activity, the determination of the level of superoxide radicals from the exposure of the whole animal and in vitro mitochondrial The point of view of the effects of cadmium on mitochondrial damage. At the same time, the use of ruthenium red (RR), cyclosporine A (CsA), dithiothreitol (DTT), EGTA tools such as medicine, to explore the mechanism of cadmium on mitochondrial damage, and cadmium-induced mitochondrial damage intervention study. Enriched by a strict mitochondrial preparation method can obtain high-purity mitochondrial components to meet the requirements of the mitochondrial samples for subsequent determination of mitochondrial function. 5 days the rat subcutaneous Cadmium experimental: 1.2 mg Cd / kg bw and 1.8 mg Cd / kg bw cadmium exposure can cause significant renal cortex mitochondrial cristae, the mitochondrial matrix vacuolization and mitochondrial swelling occurred; 1.8 mg CD / kg bw dose group as well as cellular energy supply disruptions, empty cytoplasm and lysosomes increase occurred, suggesting that the cellular level of serious injury. Rat kidney mitochondrial respiratory control ratio (RCR) values ??with cadmium exposure dose increase and decrease, and 1.8 mg Cd / kg bw dose group RCR was significantly lower than the control group; kidney mitochondrial swelling levels shown to increase with the dose of cadmium exposure and increasing trend; mitochondrial membrane potential level is increased and decreased with cadmium exposure dose, and 1.8 mg CD / kg bw dose group had significant difference; levels of free radicals with the Cadmium dose increased, and in the 1.2 mg CD / kg bw and 1.8 mg Cd / kg bw dose group was significantly higher than the control level. 12-week rat gavage subchronic cadmium exposure was found: 4 weeks Cadmium cause mitochondrial swelling and vacuolization of the renal cortex, 1.0 mg Cd / kg BW and 2.0 mg CD / kg bw dose group were severe swelling of mitochondria, matrix vacuolization pathological features, show that Cd2 serious damage to the renal cortex. Kidney mitochondrial RCR values ??showed a downward trend with increasing exposure dose and exposure time, showed that cadmium was time-dependent and dose-dependent increase the damage to the renal cortex of rats exposed to mitochondrial respiratory function. Exposed for 4 weeks, the level of kidney mitochondrial superoxide radicals increased with the increase of the exposure dose, indicating that cadmium poisoning caused by renal cortex decline antioxidant capacity and oxidative damage aggravated. Since then, the mitochondrial superoxide radical viability into with reduced mitochondrial activity decreased. Vitro rat liver, the renal mitochondria cadmium exposure experiment found: Cd2 showed a dose-dependent inhibition of the liver, kidney mitochondria RCR value; Cd2 dose-dependent induced liver, kidney swelling of mitochondria. EC50 of 8.27μM and 16.27μM, maximum swelling rate of about 40% and 30%, respectively; cause liver mitochondrial swelling Comparison of the Effects of Cd2 and Ca2 CD2 and Ca2 can dose-dependent manner to cause liver mitochondrial swelling, EC50 of 8.27μM and 47.43μM. The maximum swelling rate of about 40% and 25%; CD2 dose-dependent manner to cause liver, kidney mitochondrial membrane potential dissipation The EC50 values ??10.55μM and 26.83μM. Cd2 inhibition of rat liver, the kidney mitochondria vibrant EC50 values ??of 8.27μM and 7.73μM. These results suggest that the liver mitochondria Cd2 damage is more sensitive than the kidney mitochondrial. Research tool for drug intervention role found: the calcium uniporter blockers RR could significantly inhibit each dose of calcium and low-dose (10μM) Cd2 caused by the effects of mitochondrial swelling and membrane potential dissipation, with the CD2 dose increased RR of the blocking effect gradually weakened. Mitochondrial permeability transition pore (MPTP) blockers CsA can effectively inhibit the different concentrations of Ca2 cause liver mitochondrial swelling effect, but liver mitochondrial damage caused by Cd2 is only part of the inhibitory effect of Cd2 induced kidney mitochondrial swelling almost ineffective. In liver mitochondria, CsA can be effective against 20μM CD2 membrane potential dissipation caused by CsA void, but in kidney mitochondria, suggesting that Cd2 different organs mitochondrial damage difference. Sulfhydryl protecting agent DTT dose-dependent manner significantly reduce the Cd2-induced liver mitochondrial swelling effect, such as dose inhibition caused by Cd2 membrane potential dissipation and the corresponding inhibition of Cd2 mitochondrial activity. Calcium chelator EGTA in a dose-dependent decrease in 10μM Cd2 effect of swelling of mitochondria membrane potential dissipation and mitochondrial activity. In summary, this study confirmed kidney mitochondria important target site for cadmium injury, cadmium can cause ultrastructural changes of the renal cortex, and cause damage to the kidney mitochondrial respiratory function, activity decreased in the whole animal experiments. In vitro experiments showed that cadmium dose-dependent inhibition of the liver, kidney mitochondrial respiratory function, causing swelling of mitochondria, mitochondrial membrane potential dissipation and mitochondrial activity decreased. Cadmium injury obvious differences in organ, the liver mitochondria of cadmium injury is more sensitive than the kidney mitochondria. Cadmium mainly through the mitochondrial calcium channel into the mitochondria, causing mitochondrial permeability pore opening. Nail red at certain concentrations effective in blocking cadmium injury, CsA can also be suppressed to some extent effects of cadmium injuries. Cadmium can also toxic damage by binding to protein thiol DTT can to a certain extent against cadmium injury; EGTA to eliminate cadmium injury can be to a certain extent. DTT intervention effect is slightly better than EGTA. These tools Determination of the effects of drugs provides useful insights for effective interventions cadmium injury.

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