Liver-derived exosome-laden lncRNA MT1DP aggravates cadmium-induced nephrotoxicity

Ming Gao; Zheng Dong; Jinfang Sun; Wei Liu; Ming Xu; Changying Li; Pan Zhu; Xingfeng Yang; Xiaohong Shang; Yongning Wu; Sijin Liu

doi:10.1016/j.envpol.2019.113717

Liver-derived exosome-laden lncRNA MT1DP aggravates cadmium-induced nephrotoxicity

Environ Pollut. 2020 Mar:258:113717. doi: 10.1016/j.envpol.2019.113717. Epub 2019 Dec 14.

Authors

Ming Gao¹, Zheng Dong¹, Jinfang Sun², Wei Liu¹, Ming Xu¹, Changying Li³, Pan Zhu⁴, Xingfeng Yang⁵, Xiaohong Shang⁶, Yongning Wu⁷, Sijin Liu⁸

Affiliations

¹ State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China.
³ State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
⁴ Guangdong Provincial Center of Disease Control and Prevention, Qujiang City Guangzhou, 511430, Southern China.
⁵ Guangdong Provincial Center of Disease Control and Prevention, Qujiang City Guangzhou, 511430, Southern China; Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, 100022, China.
⁶ 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.
⁷ Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, 100022, China; 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. Electronic address: wuyongning@cfsa.net.cn.
⁸ State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: sjliu@rcees.ac.cn.

PMID: 31864927
DOI: 10.1016/j.envpol.2019.113717

Abstract

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.

Keywords: Cadmium; Exosomes; LncRNA; MT1DP; Nephrotoxicity.

MeSH terms

Apoptosis
Cadmium / toxicity*
China
Exosomes*
Humans
Kidney / drug effects*
Liver*
Metallothionein / genetics
RNA, Long Noncoding / genetics*

Substances

RNA, Long Noncoding
Cadmium
Metallothionein