Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity

Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT−/−) and corresponding wild-type (MT+/+) mice was investigated to determine any associations with MT. Each MT−/− or MT+/+ mouse was pretreated with a single dose of DU (10mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT−/− mice significantly increased than in MT+/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT−/− mice. The apoptosis rate in MT−/− mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT−/− mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT−/− mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression. •MT−/− and MT+/+ mice were used to evaluate nephrotoxicity of DU.•Renal damage was more evident in the MT−/− mice after exposure to DU.•Exogenous MT also protects against DU-induced nephrotoxicity.•MT deficiency induced more ROS and apoptosis after exposure to DU.•MT deficiency down-regulated SGLT expression after exposure to DU.