Abstract
The purpose of this study was to investigate the underlying mechanism of metallothionein (MT) protection from depleted uranium (DU) using a proteomics approach to search for a DU toxicity-differential protein. MT−/− and MT+/+ mice were administrated with a single dose of DU (10 mg/kg, i.p.) or equal volume of saline. After 4 days, protein changes in kidney tissues were evaluated using a proteomics approach. A total of 13 differentially expressed proteins were identified using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The validating results showed that the expression of aminoacylase-3 (ACY-3) and the mitochondrial ethylmalonic encephalopathy 1 (ETHE1) decreased significantly after DU exposure; in addition, the reduction in MT−/− mice was more significant than that in MT+/+ mice. The results also showed that exogenous ETHE1 or ACY-3 could increase the survival rate of human embryonic kidney 293 (HEK293) cells after DU exposure. A specific siRNA of ETHE1 significantly increased cell apoptosis rates after DU exposure, whereas exogenous ETHE1 significantly decreased cell apoptosis rates. In summary, ACY-3 and ETHE1 might involve in protection roles of MT. ETHE1 could be a new sensitive molecular target of DU-induced cell apoptosis.
Highlights
Metallothionein (MT) is a family of low molecular weight, sulphur-containing proteins and plays an important role in metal metabolism and protects cells against the toxic effects of radiation, alkylating agents and oxygen free radicals[15]
To investigate the molecular mechanism underlying the enhanced Depleted uranium (DU) sensitivity observed after MT knockout, the differences in protein samples from kidney tissues collected after exposure of MT+/+mice and MT−/−mice to DU or normal saline for 4 d were evaluated using 2-DE
The proteomics approach applied in this study identified a total 13 differentially expressed proteins based on a greater than 2-fold difference in expression and a Mascot search score higher than 64
Summary
Metallothionein (MT) is a family of low molecular weight, sulphur-containing proteins and plays an important role in metal metabolism and protects cells against the toxic effects of radiation, alkylating agents and oxygen free radicals[15]. Further study[17] showed that MT-knockout mice (MT−/−)display significantly higher serum creatinine and urea nitrogen, severe pathological injury, a significant reduction of the activity of anti-superoxide anion free radicals, catalase, glutathione peroxidase, and superoxide dismutase, and increased levels of malondialdehyde after DU exposure compared with wild-type mice (MT+/+). These results suggested that MT might play critical roles in antagonizing DU-induced nephrotoxicity, leading to new perspectives regarding the prevention and treatment of DU-induced injury. The differences in protein expression in kidney tissues following DU exposure in MT−/−mice and MT+/+mice were analysed to investigate the mechanism of action underlying DU-induced nephrotoxicity and the protective function of MT, to obtain many clues regarding DU intoxication and the protection mechanism of MT
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