单位：[a]State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China[b]University of Chinese Academy of Sciences, Beijing, 100049, China[c]Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China[d]Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China临床科室国家中心肝病分中心首都医科大学附属北京友谊医院[e]Guangdong Provincial Center of Disease Control and Prevention, Qujiang City Guangzhou, 511430, Southern China[f]Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, 100022, China[g]NHC Key Laboratory for Food Safety Risk Assessment, Food Safety Research Unit (2019RU014) of Chinese Academy of Medical Science, China National Centre for Food Safety Risk Assessment, Beijing, 100022, China
Cadmium (Cd) is a well-characterized toxic heavy metal which could cause severe kidney injury. However, currently the knowledge of Cd toxicity towards kidney is still insufficient. Our previous data has identified that MT1DP (metallothionein 1D pseudogene) could promote Cd-induced detrimental effects on hepatocytes. Herein, we further found that MT1DP was also an important intermediate to aggravate Cd-induced nephrotoxicity. Through analyzing the data of 100 residents from Cd-contaminated area in Southern China, we found that the blood MT1DP levels correlated to the urine Cd content and the extent of nephrotoxicity. Although MT1DP was predominantly induced by hepatocytes in the liver, liver-secreted MT1DP was found to be packaged into extracellular cargoes: exosomes, by which MT1DP was delivered into circulation and thereafter targeted kidney cells. Furthermore, exosome-laden MT1DP worsened Cd-induced nephrotoxicity, as evidenced in both Cd-poisoned individuals and in vitro cells. Moreover, MT1DP was found to reinforce Cd-induced toxicity in kidney cells by indirectly breaking the equilibrium between the pro-apoptotic and anti-apoptotic effects conducted by BAX and Bcl-xL, respectively. Collectively, our data unveiled that hepatocyte-derived MT1DP depends on the delivery of exosomes to wreak considerable havoc in Cd nephrotoxicity. This study offers new insights into the molecular mechanisms of Cd-induced kidney injury. (C) 2019 Elsevier Ltd. All rights reserved.
基金：
Strategic Priority Research Program of the Chinese Academy of SciencesChinese Academy of Sciences [XDB14000000]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21425731, 21637004, 81325017, 81573159]; Special Public Welfare Fund of Health Research, National Health Commission (NHC) [201302005, 200202009]
第一作者单位：[a]State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China[b]University of Chinese Academy of Sciences, Beijing, 100049, China
通讯作者：
通讯机构：[a]State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China[b]University of Chinese Academy of Sciences, Beijing, 100049, China[f]Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, 100022, China[g]NHC Key Laboratory for Food Safety Risk Assessment, Food Safety Research Unit (2019RU014) of Chinese Academy of Medical Science, China National Centre for Food Safety Risk Assessment, Beijing, 100022, China[*1]State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.[*2]Guangdong Provincial Center of Disease Control and Prevention, Qujiang City Guangzhou, 511430, Southern China.
环境科学与生态学