title: Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity.
abstract: 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.
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
authors.forename: Zhangyou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Science, 20 Dongdajie Street, Fengtai District, Beijing 100071, China.
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: wwdwyl@sina.com.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China. Electronic address: yuhui_hao@126.com.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000172:deficiency* / Q000235:genetics; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D051247:Sodium-Glucose Transport Proteins / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014502:Uranyl Nitrate
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C491054:Mt2 protein, mouse; D017382:Reactive Oxygen Species; D051247:Sodium-Glucose Transport Proteins; D014502:Uranyl Nitrate; D008668:Metallothionein; D003404:Creatinine
keywords: Apoptosis; Depleted uranium; Metallothionein; Nephrotoxicity; Oxidative stress; Sodium-glucose cotransporter